Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof

ABSTRACT

The invention relates to the compounds of formula (I) and to the physiologically acceptable salts thereof. Said compounds are suitable e.g. for the treatment of hyperglycemia.

Tetrasubstituted oxathiazine derivatives, method for producing them,their use as medicine and drug containing said derivatives and the usethereof.

The invention relates to substituted oxathiazine derivatives and to thephysiologically compatible salts thereof.

It was an object of the invention to provide compounds which display atherapeutically utilizable action. More particularly, it was a furtherobject to find novel compounds suitable for treatment of diabetes,hyperglycemia, insulin resistance, obesity or lipid metabolismdisorders.

The invention therefore relates to the compound of the formula I

in which

-   L is R1, —CH(R10)(R11);-   R10, R11 are each independently H, F, Cl, Br, I, OH, CF₃, CHF₂,    CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,    NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl, CONH₂,    CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅, (C₁-C₆)-alkylene-(R6),    (C₃-C₈)-cycloalkylene-(R6),    (C₁-C₆)-alkylene-(C₃-C₈)-cycloalkylene-(R6), (C₆-C₁₀)-aryl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, —(C₆-C₁₀)-heteroaryl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-heteroaryl;    -   where the aryl radical or heteroaryl radical may be mono- to        trisubstituted by F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN,        OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,        SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,        COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,        CON((C₁-C₆)-alkyl)₂, SF₅;-   R6 is OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl,    (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃,    SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,    COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂,    SF₅;-   R1 is (C₆-C₁₀)-aryl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-carbocyclyl,    -   where the aryl radical, cycloalkyl radical or carbocyclyl        radical may be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃,        CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,        SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,        COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,        CON((C₁-C₆)-alkyl)₂, SF₅;-   R2, R3, R4, R5 are each independently (C₁-C₆)-alkyl, CF₃, CHF₂,    CH₂F, (C₁-C₆)-alkylene-OH, (C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    (C₆-C₁₀)-aryl, (C₁-C₆)-alkylene-O—(C₆-C₁₀)-aryl, or R2 and R3 or R4    and R5, together with the carbon atom to which they are bonded form    a 3-8-membered saturated carbocyclic or heterocyclic ring which may    contain up to 2 further heteroatoms from the group of N, O and S;    and pharmaceutically acceptable salts thereof.

Preference is given to compounds of the formula I in which:

-   L is R1, —CH(R10)(R11);-   R10, R11 are each independently F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F,    NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,    NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl, CONH₂,    CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅, (C₁-C₆)-alkylene-(R6),    (C₃-C₈)-cycloalkylene-(R6),    (C₁-C₆)-alkylene-(C₃-C₈)-cycloalkylene-(R6), (C₆-C₁₀)-aryl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, —(C₆-C₁₀)-heteroaryl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-heteroaryl;    -   where the aryl radical or heteroaryl radical may be mono- to        trisubstituted by F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN,        OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,        SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,        COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,        CON((C₁-C₆)-alkyl)₂, SF₅;-   R6 is OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl,    (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃,    SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,    COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂,    SF₅;-   R1 is (C₃-C₈)-cycloalkyl, (C₃-C₈)-carbocyclyl,    -   where the cycloalkyl radical or carbocyclyl radical may be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN,        OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,        SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,        COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,        CON((C₁-C₆)-alkyl)₂, SF₅;-   R2, R3, R4, R5 are each independently (C₁-C₆)-alkyl, CF₃,    (C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl or R2 and R3, or R4 and R5,    together with the carbon atom to which they are bonded form a    3-8-membered saturated carbocyclic or heterocyclic ring which may    contain up to 2 further heteroatoms from the group of N, O and S;    and pharmaceutically acceptable salts thereof.

Preference is further given to compounds of the formula I in which:

-   L is R1, —CH(R10)(R11);-   R10, R11 are each independently (C₁-C₆)-alkyl,    (C₁-C₆)-alkylene-(R6), (C₆-C₁₀)-aryl, (C₆-C₁₀)-heteroaryl;    -   where the aryl radical or heteroaryl radical may be mono- to        trisubstituted by F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN,        OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,        SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,        COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,        CON((C₁-C₆)-alkyl)₂, SF₅;-   R6 is OH, SO₂—NH₂;-   R1 is (C₃-C₈)-cycloalkyl, (C₃-C₈)-carbocyclyl,    -   where the cycloalkyl radical or carbocyclyl radical may be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN,        OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,        SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,        COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,        CON((C₁-C₆)-alkyl)₂, SF₅;-   R2, R3, R4, R5 are each independently (C₁-C₆)-alkyl, CF₃,    (C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl or R2 and R3, or R4 and R5,    together with the carbon atom to which they bonded form a    3-8-membered saturated carbocyclic or heterocyclic ring which may    contain up to 2 further heteroatoms from the group of N, O and S;    and pharmaceutically acceptable salts thereof.

Preference is further given to compounds of the formula I in which:

-   L is R1, —CH(R10)(R11);-   R10 is (C₁-C₆)-alkylene-(R6),-   R11 is (C₆-C₁₀)-aryl, (C₆-C₁₀)-heteroaryl,    -   where the aryl radical or heteroaryl radical may be mono- to        trisubstituted by F, Cl, Br, CN;-   R6 is OH, SO₂—NH₂;-   R1 is (C₃-C₈)-cycloalkyl, (C₃-C₈)-carbocyclyl,    -   where the cycloalkyl radical or carbocyclyl radical may be mono-        to trisubstituted by F, Cl, Br, OH;-   R2, R3 are each independently (C₁-C₆)-alkyl, CF₃,    (C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl or R2 and R3 together with the    carbon atom to which they bonded form a 3-8-membered saturated    carbocyclic or heterocyclic ring which may contain up to 2 further    heteroatoms from the group of N, O and S;-   R4, R5 are each independently (C₁-C₆)-alkyl, CF₃,    (C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, or R4 and R5 together with the    carbon atom to which they are bonded form a 3-8-membered saturated    carbocyclic ring;    and pharmaceutically acceptable salts thereof.

If radicals or substituents occur more than once in the compounds of theformula I (for example R6), they may each independently be defined asspecified and be the same or different.

The invention relates to compounds of the formula I in the form of theirtautomers, racemates, racemic mixtures, stereoisomer mixtures, purestereoisomers, diastereoisomer mixtures and pure diastereoisomers. Themixtures are separated, for example, by a chromatographic route.

Owing to their higher water solubility compared to the starting or basecompounds, pharmaceutically acceptable salts are particularly suitablefor medical applications. These salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the compounds of the invention are salts of inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,metaphosphoric acid, nitric acid and sulfuric acid, and of organicacids, for example acetic acid, benzenesulfonic acid, benzoic acid,citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolicacid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malicacid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid andtartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts),trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine,lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion, for exampletrifluoroacetate, likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The inventive compounds may also exist in various polymorphic forms, forexample as amorphous and crystalline polymorphic forms. All polymorphicforms of the inventive compounds are within the scope of the inventionand are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and the salts andsolvates thereof, as described herein.

An alkyl radical is understood to mean a straight-chain or branchedhydrocarbon chain having one free valence, for example methyl, ethyl,isopropyl, tert-butyl, hexyl, heptyl, octyl. The alkyl radicals may bemono- or polysubstituted as described above.

An alkylene radical is understood to mean a straight-chain or branchedhydrocarbon chain having two free valences, for example methylene,ethylene, isopropylene, tert-butylene, hexylene, heptylene, octylene.The alkylene radicals may be mono- or polysubstituted as describedabove.

A carbocycle or carbocyclyl radical is understood to mean a ring insaturated or partially unsaturated form (with one or two double bonds),formed exclusively from carbon atoms.

An aryl radical is understood to mean a phenyl, naphthyl, biphenyl,tetrahydronaphthyl, alpha- or beta-tetralonyl, indanyl or indan-1-onylradical.

The aryl radicals may be mono- or polysubstituted by suitable groups asdescribed above.

“Heterocycle” and “heterocyclic radical” are understood to mean ringsand ring systems which, apart from carbon, also contain heteroatoms, forexample nitrogen, oxygen or sulfur. In addition, this definition alsoincludes ring systems in which the heterocycle or the heterocyclicradical is fused to a further ring or ring system. The heterocycle orthe heterocyclic radical may be saturated, partly saturated or aromatic.

Suitable “heterocycles” or “heterocyclic radicals” are acridinyl,azepanyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]-tetrahydrofuran,5,6-dihydro-4H-cyclopentathiazol-2-yl, 4,5-dihydrothiazol-2-yl, furyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,4,5,6,7-tetrahydrobenzooxazol-2-yl,4,5,6,7-tetrahydro-benzothiazol-2-yl,4,5,6,7-tetrahydrobenzoimidazol-2-yl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-yl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazinyl, triazolyl,tetrazolyl, thiazolo[4,5-b]pyridinyl, thieno[2,3-d]thiazol-2-yl,tropanyl and xanthenyl.

The heterocycles or heterocyclic radicals may be mono- orpolysubstituted by suitable groups as described above.

The compound(s) of the formula I can also be administered in combinationwith further active ingredients.

The amount of a compound of the formula I required to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.3 mg to 100 mg (typically from 3 mg to50 mg) per day and per kilogram of body weight, for example 3-10mg/kg/day. An intravenous dose may be, for example, in the range from0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram per minute. Suitable infusion solutions forthese purposes may contain, for example, 0.1 ng to 10 mg, typically 1 ngto 10 mg, per milliliter. Single doses may contain, for example, 1 mg to10 g of the active ingredient. Thus, ampoules for injections maycontain, for example, from 1 mg to 100 mg, and orally administrablesingle-dose formulations, for example tablets or capsules, may contain,for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. Fortreatment of the abovementioned conditions, the compounds of the formulaI themselves may be used as the compound, but they are preferablypresent with a compatible carrier in the form of a pharmaceuticalcomposition. The carrier must of course be acceptable in the sense thatit is compatible with the other constituents of the composition and isnot harmful to the patient's health. The carrier may be a solid or aliquid or both and is preferably formulated with the compound as asingle dose, for example as a tablet, which may contain from 0.05% to95% by weight of the active ingredient. Other pharmaceutically activesubstances may likewise be present, including other compounds of formulaI. The pharmaceutical compositions of the invention can be produced byone of the known pharmaceutical methods, which essentially consist ofmixing the ingredients with pharmacologically acceptable carriers and/orexcipients.

Inventive pharmaceutical compositions are those suitable for oral,rectal, topical, peroral (for example sublingual) and parenteral (forexample subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations are also within the scope of the invention. Preference isgiven to acid- and gastric juice-resistant formulations. Suitablegastric juice-resistant coatings comprise cellulose acetate phthalate,polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate andanionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units, for example capsules, cachets, lozenges ortablets, each of which contains a defined amount of the compound offormula I; as powders or granules; as solution or suspension in anaqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilemulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingredient and the carrier (which may consist of one or moreadditional ingredients) are brought into contact. The compositions aregenerally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. For example, a tablet can beproduced by compressing or molding a powder or granules of the compound,where appropriate with one or more additional ingredients. Compressedtablets can be produced by tableting the compound in free-flowing formsuch as, for example, a powder or granules, where appropriate mixed witha binder, glidant, inert diluent and/or one (or more)surfactant(s)/dispersant(s) in a suitable machine. Molded tablets can beproduced by molding the pulverulent compound moistened with an inertliquid diluent in a suitable machine.

Pharmaceutical compositions suitable for peroral (sublingual)administration include lozenges which contain a compound of formula Iwith a flavoring, typically sucrose, and gum arabic or tragacanth, andpastilles which comprise the compound in an inert base such as gelatinand glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectable inventivecompositions generally contain from 0.1 to 5% by weight of the activecompound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula I with one or more conventionalsolid carriers, for example cocoa butter, and shaping the resultingmixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of 0.1 to15% by weight of the composition, for example 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses may be in the form of single patches whichare suitable for long-term close contact with the patient's epidermis.Such patches suitably contain the active ingredient in an aqueoussolution which is buffered where appropriate, dissolved and/or dispersedin an adhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. Aparticular option is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

Further suitable active ingredients for the combination products are:

All antidiabetics mentioned in the Rote Liste 2009, chapter 12; allweight-reducing agents/appetite suppressants mentioned in the Rote Liste2009, chapter 1; all diuretics mentioned in the Rote Liste 2009, chapter36; all lipid-lowering agents mentioned in the Rote Liste 2009, chapter58. They can be combined with the inventive compound of the formula I,especially for a synergistic improvement in action. The activeingredient combination can be administered either by separateadministration of the active ingredients to the patient or in the formof combination products in which a plurality of active ingredients arepresent in one pharmaceutical preparation. When the active ingredientsare administered by separate administration of the active ingredients,this can be done simultaneously or successively. Most of the activeingredients mentioned hereinafter are disclosed in the USP Dictionary ofUSAN and International Drug Names, US Pharmacopeia, Rockville 2006.

Antidiabetics include insulin and insulin derivatives, for exampleLantus® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir),Humalog® (Insulin Lispro), Humulin®, VIAject™, or those as described inWO2005005477 (Novo Nordisk), fast-acting insulins (see U.S. Pat. No.6,221,633), inhalable insulins, for example Exubera®, Nasulin™, or oralinsulins, for example IN-105 (Nobex) or Oral-lyn™ (GenerexBiotechnology), or Technosphere® Insulin (MannKind) or Cobalamin™ oralinsulin, or insulins as described in WO2007128815, WO2007128817, orinsulins which can be administered transdermally;

GLP-1 derivatives and GLP-1 agonists, for example exenatide,liraglutide, or those which have been disclosed in WO 98/08871,WO2005027978, WO2006037811, WO2006037810 by Novo Nordisk AIS, in WO01/04156 by Zealand or in WO 00/34331 by Beaufour-Ipsen, pramlintideacetate (Symlin; Amylin Pharmaceuticals), AVE-0010, BIM-51077 (R-1583,ITM-077), PC-DAC:Exendin-4 (an exendin-4 analog which is bondedcovalently to recombinant human albumin), CVX-73, CVX-98 and CVx-96(GLP-1 analog which is bonded covalently to a monoclonal antibody whichhas specific binding sites for the GLP-1 peptide), CNTO-736 (a GLP-1analog which is bonded to a domain which includes the Fc portion of anantibody), PGC-GLP-1 (GLP-1 bonded to a nanocarrier), agonists, asdescribed, for example, in D. Chen et al., Proc. Natl. Acad. Sci. USA104 (2007) 943, those as described in WO2006124529, WO2007124461,peptides, for example obinepitide (TM-30338), amylin receptor agonists,as described, for example, in WO2007104789, analogs of the human GLP-1,as described in WO2007120899, and orally active hypoglycemicingredients.

Antidiabetics also include agonists of the glucose-dependentinsulinotropic polypeptide (GIP) receptor, as described, for example, inWO2006121860.

Antidiabetics also include analogs and derivatives of fibroblast growthfactor 21 (FGF-21).

The orally active hypoglycemic ingredients preferably includesulfonylureas,

biguanidines,

meglitinides,

oxadiazolidinediones,

thiazolidinediones,

PPAR and RXR modulators,

glucosidase inhibitors,

inhibitors of glycogen phosphorylase,

glucagon receptor antagonists,

glucokinase activators,

inhibitors of fructose 1,6-bisphosphatase,

modulators of glucose transporter 4 (GLUT4),

inhibitors of glutamine:fructose-6-phosphate amidotransferase (GFAT),

GLP-1 agonists,

potassium channel openers, for example pinacidil, cromakalim, diazoxide,or those as described in R. D. Can et al., Diabetes 52, 2003, 2513-2518,in J. B. Hansen et al., Current Medicinal Chemistry 11, 2004, 1595-1615,in T. M. Tagmose et al., J. Med. Chem. 47, 2004, 3202-3211 or in M. J.Coghlan et al., J. Med. Chem. 44, 2001, 1627-1653, or those which havebeen disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A/S,

active ingredients which act on the ATP-dependent potassium channel ofthe beta cells,

inhibitors of dipeptidyl peptidase-W (DPP-IV),

insulin sensitizers,

inhibitors of liver enzymes involved in stimulating gluconeogenesisand/or glycogenolysis,

modulators of glucose uptake, of glucose transport and of glucosereabsorption,

modulators of sodium-dependent glucose transporter 1 or 2 (SGLT1,SGLT2),

inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11β-HSD1),

inhibitors of protein tyrosine phosphatase-1B (PTP-1B),

nicotinic acid receptor agonists,

inhibitors of hormone-sensitive or endothelial lipases,

inhibitors of acetyl-CoA carboxylase (ACC1 and/or ACC2) or

inhibitors of GSK-3 beta.

Also included are compounds which modify the lipid metabolism, such asactive antihyperlipidemic ingredients and active antilipidemicingredients,

HMG-CoA reductase inhibitors,

farnesoid X receptor (FXR) antagonists,

fibrates,

cholesterol reabsorption inhibitors,

CETP inhibitors,

bile acid absorption inhibitors,

MTP inhibitors,

estrogen receptor gamma agonists (ERR agonists),

sigma-1 receptor antagonists,

antagonists of the somatostatin 5 receptor (SST5 receptor);

compounds which reduce food intake, and

compounds which increase thermogenesis.

In one embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In one embodiment, the compound of the formula I is administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, for example sulfonylureas, forexample tolbutamide, glibenclamide, glipizide, gliclazide orglimepiride.

In one embodiment, the compound of the formula I is administered incombination with a tablet which comprises both glimepiride, which isreleased rapidly, and metformin, which is released over a longer period(as described, for example, in US2007264331).

In one embodiment, the compound of the formula I is administered incombination with a biguanide, for example metformin.

In another embodiment, the compound of the formula I is administered incombination with a meglitinide, for example repaglinide, nateglinide ormitiglinide.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with a glitazone, e.g. pioglitazonehydrochloride.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with an alpha-glucosidase inhibitor.

In a further embodiment, the compound of the formula I is administeredin combination with antidiabetic compounds, as described inWO2007095462, WO2007101060, WO2007105650.

In a further embodiment, the compound of the formula I is administeredin combination with antihypoglycemic compounds, as described inWO2007137008.

In one embodiment, the compound of the formula I is administered incombination with a thiazolidinedione, for example troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 by Dr. Reddy's Research Foundation, especially5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR gamma agonist, for examplerosiglitazone, pioglitazone, JTT-501, G1 262570, R-483, CS-011(rivoglitazone), DRL-17564, DRF-2593 (balaglitazone), or those asdescribed in WO2007060992, WO2007100027, WO2007103252, WO2007122970.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Competact™, a solid combination ofpioglitazone hydrochloride with metformin hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Tandemact™, a solid combination ofpioglitazone with glimepiride. In a further embodiment of the invention,the compound of the formula I is administered in combination with asolid combination of pioglitazone hydrochloride with an angiotensin IIagonist, for example TAK-536.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR alpha agonist or mixed PPARalpha/PPAR delta agonist, for example GW9578, GW-590735, K-111, LY-674,KRP-101, DRF-10945, LY-518674, CP-900691, BMS-687453, BMS-711939, orthose as described in WO2001040207, WO2002096894, WO2005097076,WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515,WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR alpha/gamma agonist, forexample naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134,AVE 0847, CKD-501 (lobeglitazone sulfate), MBX-213, or as described inWO 00/64888, WO 00/64876, WO03/020269, WO2007099553, US2007276041,WO2007085135, WO2007085136, or in J. P. Berger et al., TRENDS inPharmacological Sciences 28(5), 244-251, 2005.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR delta agonist, for exampleGW-501516, or as described in WO2006059744, WO2006084176, WO2006029699,WO2007039172, WO2007039178, WO2007071766, WO2007101864, US2007244094,WO2007119887.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a pan-SPPARM (selective PPAR modulatoralpha, gamma, delta), for example GFT-505.

In one embodiment, the compound of the formula I is administered incombination with metaglidasen or with MBX-2044 or other partial PPARgamma agonists/antagonists.

In one embodiment, the compound of the formula I is administered incombination with an α-glucosidase inhibitor, for example miglitol oracarbose, or those as described, for example, in WO2007114532,WO2007140230.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen phosphorylase, for examplePSN-357 or FR-258900, or those as described in WO2003084922,WO2004007455, WO2005073229-31, WO2005067932.

In one embodiment, the compound of the formula I is administered incombination with glucagon receptor antagonists, for example A-770077 orNNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488,WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581,WO2007136577.

In a further embodiment, the compound of the formula I is administeredin combination with an antisense compound, e.g. ISIS-325568, whichinhibits the production of the glucagon receptor.

In one embodiment, the compound of the formula I is administered incombination with activators of glucokinase, for example LY-2121260(WO2004063179), PSN-105, PSN-110, GKA-50, or those as described, forexample, in WO2004072031, WO2004072066, WO2005080360, WO2005044801,WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549,WO2007017649, WO2007007910, WO2007007040-42, WO2007006760-61,WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365,WO2007041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846,WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO2007075847,WO2007089512, WO2007104034, WO2007117381, WO2007122482, WO2007125103,WO2007125105, US2007281942.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of gluconeogenesis, for example FR-225654.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of fructose 1,6-bisphosphatase (FBPase), forexample CS-917 (MB-06322) or MB-07803, or those as described inWO2006023515, WO2006104030, WO2007014619, WO2007137962.

In one embodiment, the compound of the formula I is administered incombination with modulators of glucose transporter 4 (GLUT4), forexample KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12),835 (2004)).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of glutamine:fructose-6-phosphateamidotransferase (GFAT), as described, for example, in WO2004101528.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of dipeptidyl peptidase IV (DPP-IV), forexample vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptinphosphate, saxagliptin (BMS-477118), GSK-823093, PSN-9301, SYR-322,SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP-104, DP-893,ABT-341, ABT-279 or another salt thereof, S-40010, S-40755, PF-00734200,BI-1356, PHX-1149, alogliptin, or those compounds as described inWO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828,WO2005058901, WO2005012312, WO2005/012308, WO2006039325, WO2006058064,WO2006015691, WO2006015701, WO2006015699, WO2006015700, WO2006018117,WO2006099943, WO2006099941, JP2006160733, WO2006071752, WO2006065826,WO2006078676, WO2006073167, WO2006068163, WO2006085685, WO2006090915,WO2006104356, WO2006127530, WO2006111261, WO2007015767 (LY-2463665),WO2007024993, WO2007029086, WO2007063928, WO2007070434, WO2007071738,WO2007077508, WO2007087231, WO2007097931, WO2007099385, WO2007100374,WO2007112347, WO2007112669, WO2007113226, WO2007113634, WO2007115821,WO2007116092, US2007259900, EP1852108, US2007270492, WO2007126745,WO2007136603.

In one embodiment, the compound of the formula I is administered incombination with Janumet™, a solid combination of sitagliptin phosphatewith metformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with Eucreas®, a solid combination of vildagliptin withmetformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-IV inhibitor with omega-3 fattyacids or omega-3 fatty acid esters, as described, for example, inWO2007128801.

In one embodiment, the compound of the formula I is administered incombination with a substance which enhances insulin secretion, forexample KCP-265 (WO2003097064), or those as described in WO2007026761.

In one embodiment, the compound of the formula I is administered incombination with agonists of the glucose-dependent insulinotropicreceptor (GDIR), for example APD-668.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ATP citrate lyase inhibitor, forexample SB-204990.

In one embodiment, the compound of the formula I is administered incombination with modulators of the sodium-dependent glucose transporter1 or 2 (SGLT1, SGLT2), for example KGA-2727, T-1095, SGL-0010, AVE 2268,SAR 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, sergliflozin ordapagliflozin, or as described, for example, in WO2004007517,WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630,WO2005121161, WO2006018150, WO2006035796, WO2006062224, WO2006058597,WO2006073197, WO2006080577, WO2006087997, WO2006108842, WO2007000445,WO2007014895, WO2007080170, WO2007093610, WO2007126117, WO2007128480,WO2007129668, US2007275907, WO2007136116, or by A. L. Handlon in ExpertOpin. Ther. Patents (2005) 15(11), 1531-1540.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of 11-beta-hydroxysteroid dehydrogenase 1(11β-HSD1), for example BVT-2733, JNJ-25918646, INCB-13739, DIO-92((−)-ketoconazole) or those as described, for example, inWO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009,WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983,WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427,WO2004041264, WO2004037251, WO2004056744, WO2004058730, WO2004065351,WO2004089367, WO2004089380, WO2004089470-71, WO2004089896, WO2005016877,WO2005063247, WO2005097759, WO2006010546, WO2006012227, WO2006012173,WO2006017542, WO2006034804, WO2006040329, WO2006051662, WO2006048750,WO2006049952, WO2006048331, WO2006050908, WO2006024627, WO2006040329,WO2006066109, WO2006074244, WO2006078006, WO2006106423, WO2006132436,WO2006134481, WO2006134467, WO2006135795, WO2006136502, WO2006138508,WO2006138695, WO2006133926, WO2007003521, WO2007007688, US2007066584,WO2007029021, WO2007047625, WO2007051811, WO2007051810, WO2007057768,WO2007058346, WO2007061661, WO2007068330, WO2007070506, WO2007087150,WO2007092435, WO2007089683, WO2007101270, WO2007105753, WO2007107470,WO2007107550, WO2007111921, US2007207985, US2007208001, WO2007115935,WO2007118185, WO2007122411, WO2007124329, WO2007124337, WO2007124254,WO2007127688, WO2007127693, WO2007127704, WO2007127726, WO2007127763,WO2007127765, WO2007127901, US2007270424, JP2007291075, WO2007130898,WO2007135427.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of protein tyrosine phosphatase 1B (PTP-1B),as described, for example, in WO200119830-31, WO200117516, WO2004506446,WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004060542.4, WO2007009911, WO2007028145, WO2007067612-615, WO2007081755,WO2007115058.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR109A (HM74A receptoragonists; NAR agonists (nicotinic acid receptor agonists)), for examplenicotinic acid or “extended release niacin” in conjunction with MK-0524A(laropiprant) or MK-0524, or those compounds as described inWO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112,WO2006085113, WO2006124490, WO2006113150, WO2007017261, WO2007017262,WO2007017265, WO2007015744, WO2007027532, WO2007092364, WO2007120575,WO2007134986.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of niacin withsimvastatin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with nicotinic acid or “extended releaseniacin” in conjunction with MK-0524A (laropiprant).

In a further embodiment of the invention, the compound of the formula Iis administered in combination with nicotinic acid or “extended releaseniacin” in conjunction with MK-0524A (laropiprant) and with simvastatin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR116, as described, forexample, in WO2006067531, WO2006067532.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR40, as described, for example, inWO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225,WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622,WO2007136572.

In one embodiment, the compound of the formula I is administered incombination with GPR119b modulators, as described, for example, inWO2004041274.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119 (G protein-coupledglucose-dependent insulinotropic receptor), for example PSN-119-1, orthose as described, for example, in WO2005061489 (PSN-632408),WO2004065380, WO2006018662, WO2007003960-62 and WO2007003964,WO2007116229, WO2007116230.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of GPR120, as described, for example, inEP1688138.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of hormone-sensitive lipase (HSL) and/orphospholipases, as described, for example, in WO2005073199,WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of endothelial lipase, as described, forexample, in WO2007110216.

In one embodiment, the compound of the formula I is administered incombination with a phospholipase A2 inhibitor, for example darapladib orA-002.

In one embodiment, the compound of the formula I is administered incombination with myricitrin, a lipase inhibitor (WO2007119827).

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3beta), as described, for example, in US2005222220, WO2005085230,WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908,US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343,EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117,WO2007073117, WO2007083978, WO2007120102, WO2007122634, WO2007125109,WO2007125110.

In one embodiment, the compound of the formula I is administered incombination with, an inhibitor of phosphoenolpyruvate carboxykinase(PEPCK), for example those as described in WO2004074288.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of serum/glucocorticoid-regulated kinase(SGK), as described, for example, in WO2006072354, WO2007093264.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of protein kinase C beta (PKC beta), forexample ruboxistaurin.

In a further embodiment, the compound of the formula I is administeredin combination with an activator of the AMP-activated protein kinase(AMPK), as described, for example, in WO2007062568.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of ceramide kinase, as described, forexample, in WO2007112914.

In a further embodiment, the compound of the formula I is administeredin combination with an inhibitor of MAPK-interacting kinase 2 (MNK2), asdescribed, for example, in WO2007104053, WO2007115822.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of “I-kappaB kinase” (IKK inhibitors), asdescribed, for example, in WO2001000610, WO2001030774, WO2004022057,WO2004022553, WO2005097129, WO2005113544, US2007244140.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an HMG-CoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin, L-659699, or those as described inUS2007249583.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a farnesoid X receptor (FXR)antagonist, as described, for example, in WO2007052843, WO2007070796,WO2007092751, JP2007230909, WO2007095174, WO2007140174, WO2007140183.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a ligand of the liver X receptor (LXR),as described, for example, in WO2007092965.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate, for example fenofibrate,clofibrate, bezafibrate.

In one embodiment of the invention, the compound of the formula I isadministered in combination with fibrates, for example the choline saltof fenofibrate (SLV-348).

In one embodiment of the invention, the compound of the formula I isadministered in combination with fibrates, for example the choline saltof fenofibrate and an HMG-CoA reductase inhibitor, for examplerosuvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with bezafibrate and diflunisal.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a solid combination of fenofibrateor a salt thereof with simvastatin, rosuvastatin, fluvastatin,lovastatin, cerivastatin, pravastatin or atorvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with Synordia®, a solid combination offenofibrate with metformin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol absorption inhibitor, forexample ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497,WO2005021495) or with compounds as described in WO2002066464,WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 orWO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZenecaAB) and WO2006017257 (Phenomix) or WO2005033100 (Lipideon BiotechnologyAG), or as described in WO2002050060, WO2002050068, WO2004000803,WO2004000804, WO2004000805, WO2004087655, WO2004097655, WO2005047248,WO2006086562, WO2006102674, WO2006116499, WO2006121861, WO2006122186,WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782,WO2006137793, WO2006137797, WO2006137795, WO2006137792, WO2006138163,WO2007059871, US2007232688, WO2007126358.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Vytorin™, a solid combination ofezetimibe with simvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of ezetimibe withatorvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of ezetimibe withfenofibrate.

In one embodiment of the invention, the further active ingredient is adiphenylazetidinone derivative, as described, for example, in U.S. Pat.No. 6,992,067 or U.S. Pat. No. 7,205,290.

In a further embodiment of the invention, the further active ingredientis a diphenylazetidinone derivative, as described, for example, in U.S.Pat. No. 6,992,067 or U.S. Pat. No. 7,205,290, combined with a statin,for example simvastatin, fluvastatin, pravastatin, lovastatin,cerivastatin, atorvastatin or rosuvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of lapaquistat, asqualene synthase inhibitor, with atorvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor, for exampletorcetrapib, anacetrapib or JTT-705, or those as described inWO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362,WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154,US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243,WO2007120621, US2007265252, US2007265304, WO2007128568, WO2007132906.

In one embodiment of the invention, the compound of the formula I isadministered in combination with bile acid reabsorption inhibitor (see,for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 orWO00/61568), for example HMR 1741, or those as described in DE 10 2005033099.1 and DE 10 2005 033100.9, WO2007009655-56.

In one embodiment, the compound of the formula I is administered incombination with agonists of GPBAR1 (G-protein-coupled bile acidreceptor-1; TGR5), as described, for example, in WO2007110237,WO2007127505.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorber, forexample cholestyramine, colesevelam hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a chewing gum comprising phytosterols(Reductol™).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of the microsomaltriglyceride transfer protein (MTP inhibitor), for example implitapide,BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733, or those asdescribed in WO2005085226, WO2005121091, WO2006010423, WO2006113910.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an antagonist of the somatostatin 5receptor (SST5 receptor), for example those as described inWO2006094682.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor, for exampleavasimibe, SMP-797 or KY-382.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an inhibitor of liver carnitinepalmitoyltransferase 1 (L-CPT1), as described, for example, inWO2007063012, WO2007096251 (ST-3473).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor, forexample BMS-188494, TAK-475 (lapaquistat acetate), or as described inWO2005077907, JP2007022943.

In one embodiment of the invention, the compound of the formula I isadministered in combination with ISIS-301012 (mipomersen), an antisenseoligonucleotide which is capable of regulating the apolipoprotein Bgene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), for example HMR1171, HMR1586, or those as described inWO2005097738.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ABCA1 expression enhancer, asdescribed, for example, in WO2006072393.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator, forexample ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein(a) antagonist, forexample gemcabene (CI-1027).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor, for exampleorlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an adenosine A2B receptor agonist(adenosine A2B R), for example ATL-801.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a modulator of adenosine A2A and/oradenosine A3 receptors, as described, for example, in WO2007111954,WO2007121918, WO2007121921, WO2007121923.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an adenosine A2B receptor antagonist(adenosine A2B R), as described in US2007270433.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of acetyl-CoA carboxylase (ACC1 and/orACC2), for example those as described in WO199946262, WO200372197,WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809,WO2007011811, WO2007013691, WO2007095601-603, WO2007119833.

In another embodiment, the compound of the formula I is administered incombination with modulators of microsomal acyl-CoA:glycerol-3-phosphateacyltransferase 3 (GPAT3, described in WO2007100789) or with modulatorsof microsomal acyl-CoA:glycerol-3-phosphate acyltransferase 4 (GPAT4,described in WO2007100833).

In a further embodiment, the compound of the formula I is administeredin combination with modulators of xanthine oxidoreductase (XOR).

In a further embodiment, the compound of the formula I is administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9),554-558);

NPY antagonists, for example4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethylnaphthalene-1-sulfonamidehydrochloride (CGP 71683A);

NPY-5 receptor antagonists, such as L-152804 or the compound “NPY-5-BY”from Banyu, or as described, for example, in WO2006001318, WO2007103295,WO2007125952;

NPY-4 receptor antagonists, as described, for example, in WO2007038942;

NPY-2 receptor antagonists, as described, for example, in WO2007038943;

peptide YY 3-36 (PYY3-36) or analogous compounds, for example CJC-1682(PYY3-36 conjugated with human serum albumin via Cys34) or CJC-1643(derivative of PYY3-36, which is conjugated in vivo to serum albumin),or those as described in WO2005080424, WO2006095166;

derivatives of the peptide obestatin, as described by WO2006096847;

CB1R (cannabinoid receptor 1) antagonists (for example rimonabant,surinabant (SR147778), SLV-319, AVE-1625, taranabant (MK-0364) or saltsthereof, V-24343 or those compounds as described in, for example, EP0656354, WO 00/15609, WO2001/64632-64634, WO 02/076949, WO2005080345,WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700,WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069,U.S. Pat. No. 6,509,367, WO200132663, WO2003086288, WO2003087037,WO2004048317, WO2004058145, WO2003084930, WO2003084943, WO2004058744,WO2004013120, WO2004029204, WO2004035566, WO2004058249, WO2004058255,WO2004058727, WO2004069838, US20040214837, US20040214855, US20040214856,WO2004096209, WO2004096763, WO2004096794, WO2005000809, WO2004099157,US20040266845, WO2004110453, WO2004108728, WO2004000817, WO2005000820,US20050009870, WO200500974, WO2004111033-34, WO200411038-39,WO2005016286, WO2005007111, WO2005007628, US20050054679, WO2005027837,WO2005028456, WO2005063761-62, WO2005061509, WO2005077897, WO2006047516,WO2006060461, WO2006067428, WO2006067443, WO2006087480, WO2006087476,WO2006100208, WO2006106054, WO2006111849, WO2006113704, WO2007009705,WO2007017124, WO2007017126, WO2007018459, WO2007018460, WO2007016460,WO2007020502, WO2007026215, WO2007028849, WO2007031720, WO2007031721,WO2007036945, WO2007038045, WO2007039740, US20070015810, WO2007046548,WO2007047737, WO2007057687, WO2007062193, WO2007064272, WO2007079681,WO2007084319, WO2007084450, WO2007086080, EP1816125, US2007213302,WO2007095513, WO2007096764, US2007254863, WO2007119001, WO2007120454,WO2007121687, WO2007123949, US2007259934, WO2007131219, WO2007133820,WO2007136607, WO2007136571, US7297710, WO2007138050, WO2007140385,WO2007140439);

cannabinoid receptor 1/cannabinoid receptor 2 (CB1/CB2) modulatingcompounds, for example delta-9-tetrahydrocannabivarin, or those asdescribed, for example, in WO2007001939, WO2007044215, WO2007047737,WO2007095513, WO2007096764, WO2007112399, WO2007112402;

modulators of FAAH (fatty acid amide hydrolase), as described, forexample, in WO2007140005;

vanilloid 1 receptor modulators (modulators of TRPV1), as described, forexample, in WO2007091948, WO2007129188, WO2007133637;

activators of the capsaicin receptor, as described, for example, inJP2007210969;

agonists of the prostaglandin receptor, for example bimatoprost or thosecompounds as described in WO2007111806;

MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists,for exampleN-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]-pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide;(WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,CHIR-785, PT-141, MK-0493, or those as described in WO2005060985,WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720,US20050124652, WO2005051391, WO2004112793, WOUS20050222014,US20050176728, US20050164914, US20050124636, US20050130988,US20040167201, WO2004005324, WO2004037797, WO2005042516, WO2005040109,WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339,EP1460069, WO2005047253, WO2005047251, WO2005118573, EP1538159,WO2004072076, WO2004072077, WO2006021655-57, WO2007009894, WO2007015162,WO2007041061, WO2007041052, JP2007131570, EP-1842846, WO2007096186,WO2007096763;

orexin receptor 1 antagonists (OX1R antagonists), orexin receptor 2antagonists (OX2R antagonists) or mixed OX1R/OX2R antagonists (e.g.1-(2-methyl-benzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A), or those as described, for example, in WO200196302,WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718,WO2007088276, WO2007116374; WO2007122591, WO2007126934, WO2007126935);

histamine H3 receptor antagonists/inverse agonists (e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208), or those as described in WO200064884,WO2005082893, US2005171181 (e.g. PF-00389027), WO2006107661,WO2007003804, WO2007016496, WO2007020213, WO2007049798, WO2007055418,WO2007057329, WO2007065820, WO2007068620, WO2007068641, WO2007075629,WO2007080140, WO2007082840, WO2007088450, WO2007088462, WO2007094962,WO2007099423, WO2007100990, WO2007105053, WO2007106349, WO2007110364,WO2007115938, WO2007131907, WO2007133561, US2007270440, WO2007135111);

histamine H1/histamine H3 modulators, for example betahistine or itsdihydrochloride;

CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585) or those CRF1 antagonists as described in WO2007105113,WO2007133756);

CRF BP antagonists (e.g. urocortin);

urocortin agonists;

agonists of the beta-3 adrenoceptor, for example1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanolhydrochloride (WO 01/83451) or solabegron (GW-427353) or N-5984(KRP-204), or those as described in JP2006111553, WO2002038543,WO2002038544, WO2007048840-843;

MSH (melanocyte-stimulating hormone) agonists;

MCH (melanine-concentrating hormone) receptor antagonists (for exampleNBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430, orthose compounds as described in WO2005085200, WO2005019240,WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898,WO2005070925, WO2004039780, WO2004092181, WO2003033476, WO2002006245,WO2002089729, WO2002002744, WO2003004027, FR2868780, WO2006010446,WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280,WO2006018279, WO2006118320, WO2006130075, WO2007018248, WO2007012661,WO2007029847, WO2007024004, WO2007039462, WO2007042660, WO2007042668,WO2007042669, US2007093508, US2007093509, WO2007048802, JP2007091649,WO2007092416; WO2007093363-366, WO2007114902, WO2007114916);

CCK-A (CCK-1) agonists (for example{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150)or SSR-125180), or those as described in WO2005116034, WO2007120655,WO2007120688, WO2007120718;

serotonin reuptake inhibitors (for example dexfenfluramine);

mixed serotonin/dopamine reuptake inhibitors (e.g. bupropion), or solidcombinations of bupropion with naltrexone or bupropion with zonisamide;

mixed reuptake inhibitors, for example DOV-21947;

mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549);

5-HT receptor agonists, for example 1-(3-ethylbenzofuran-7-yl)piperazineoxalic acid salt (WO 01/09111);

mixed dopamine/norepinephrine/acetylcholine reuptake inhibitors (e.g.tesofensine), or those as described, for example, in WO2006085118;

5-HT2C receptor agonists (for example lorcaserine hydrochloride(APD-356) or BVT-933, or those as described in WO200077010,WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533,WO2005082859, WO2006004937, US2006025601, WO2006028961, WO2006077025,WO2006103511, WO2007028132, WO2007084622, US2007249709; WO2007132841,WO2007140213);

5-HT6 receptor modulators, for example E-6837, BVT-74316 or PRX-07034,or those as described, for example, in WO2005058858, WO2007054257,WO2007107373, WO2007108569, WO2007108742-744;

agonists of estrogen receptor gamma (ERR agonists), as described, forexample, in WO2007131005;

sigma-1 receptor antagonists, as described, for example, inWO2007098953, WO2007098961;

muscarin 3 receptor (M3R) antagonists, as described, for example, inWO2007110782;

bombesin receptor agonists (BRS-3 agonists);

galanin receptor antagonists;

growth hormone (e.g. human growth hormone or AOD-9604);

growth hormone releasing compounds (tert-butyl6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695));

growth hormone secretagogue receptor antagonists (ghrelin antagonists),for example A-778193, or those as described in WO2005030734,WO2007127457;

growth hormone secretagogue receptor modulators, for example JMV-2959,JMV-3002, JMV-2810, JMV-2951, or those as described in WO2006012577(e.g. YIL-781 or YIL-870), WO2007079239;

TRH agonists (see, for example, EP 0 462 884);

decoupling protein 2 or 3 modulators;

leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881);

dopamine agonists (DA agonists, for example bromocriptine, Doprexin);

lipase/amylase inhibitors (e.g. WO 00/40569);

inhibitors of diacylglycerol O-acyltransferases (DGATs), for exampleBAY-74-4113, or as described, for example, in US2004/0224997,WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492,WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952,WO2006120125, WO2006113919, WO2006134317, WO2007016538, WO2007060140,JP2007131584, WO2007071966, WO2007126957, WO2007137103, WO2007137107,WO2007138304, WO2007138311;

inhibitors of fatty acid synthase (FAS), for example C75, or those asdescribed in WO2004005277;

inhibitors of stearoyl-CoA delta9 desaturase (SCD1), as described, forexample in WO2007009236, WO2007044085, WO2007046867, WO2007046868,WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457,WO2007136746;

inhibitors of “adipocyte fatty acid-binding protein aP2”, for exampleBMS-309403;

activators of adiponectin secretion, as described, for example, inWO2006082978;

promoters of adiponectin production, as described, for example, inWO2007125946;

oxyntomodulin;

oleoyl-estrone

or agonists or partial agonists of the thyroid hormone receptor (thyroidhormone receptor agonists), for example: KB-2115 or DITPA, or those asdescribed in WO20058279, WO200172692, WO200194293, WO2003084915,WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125,WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864;

or agonists of the thyroid hormone receptor beta (TR-beta), for exampleMB-07811 or MB-07344.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of site-1 protease (SIP),for example PF-429242.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an RNAi therapeutic agent directedagainst PCSK9 (proprotein convertase subtilisin/kexin type 9).

In one embodiment, the compound of the formula I is administered incombination with Omacor® or Lovaza™ (omega-3 fatty acid ester; highlyconcentrated ethyl ester of eicosapentaenoic acid and of docosahexaenoicacid).

In one embodiment, the compound of the formula I is administered incombination with lycopene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant, for example OPC-14117,succinobucol, probucol, tocopherol, ascorbic acid, β-carotene orselenium.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin, for example vitamin B6 orvitamin B 12.

In one embodiment, the compound of the formula I is administered incombination with more than one of the aforementioned compounds, forexample in combination with a sulfonylurea and metformin, a sulfonylureaand acarbose, repaglinide and metformin, insulin and a sulfonylurea,insulin and metformin, insulin and troglitazone, insulin and lovastatin,etc.

In another embodiment, the compound of the formula I is administered incombination with an inhibitor of carboanhydrase type 2 (carbonicanhydrase type 2), for example those as described in WO2007065948.

In another embodiment, the compound of the formula I is administered incombination with topiramate.

In a further embodiment, the compound of the formula I is administeredin combination with a solid combination of topiramate with phentermine(Qnexa™).

In a further embodiment, the compound of the formula I is administeredin combination with an antisense compound, e.g. ISIS-377131, whichinhibits the production of the glucocorticoid receptor.

In one embodiment, the compound of the formula I is administered incombination with an agonist of the RUP3 receptor, as described, forexample, in WO2007035355.

In another embodiment, the compound of the formula I is administered incombination with an activator of the gene which codes for ataxiatelangiectasia mutated (ATM) protein kinase, for example chloroquine.

In one embodiment, the compound of the formula I is administered incombination with a tau protein kinase 1 inhibitor (TPK1 inhibitor), asdescribed, for example, in WO2007119463.

In one embodiment, the compound of the formula I is administered incombination with a “c-Jun N-terminal kinase” inhibitor (INK inhibitor),as described, for example, in WO2007125405.

In one embodiment, the compound of the formula I is administered incombination with an endothelin A receptor antagonist, for exampleavosentan (SPP-301).

In one embodiment, the compound of the formula I is administered incombination with modulators of the glucocorticoid receptor (GR), forexample KB-3305 or those compounds as described, for example, inWO2005090336, WO2006071609, WO2006135826, WO2007105766.

In one embodiment, the further active ingredient is vareniclinetartrate, a partial agonist of the alpha 4-beta 2 nicotinicacetylcholine receptor.

In one embodiment, the further active ingredient is trodusquemine

In one embodiment, the further active ingredient is a modulator of theenzyme SIRT1 (an NAD⁺-dependent protein deacetylase); this activeingredient may, for example, be resveratrol in suitable formulations, orthose compounds as specified in WO2007019416 (e.g. SRT-1720).

In one embodiment of the invention, the further active ingredient isDM-71 (N-acetyl-L-cysteine with bethanechol).

In one embodiment, the compound of the formula I is administered incombination with antihypercholesterolemic compounds, as described, forexample, in WO2007107587, WO2007111994.

In another embodiment, the compound of the formula I is administered incombination with a cyclic peptide agonist of the VPAC2 receptor, asdescribed, for example, in WO2007101146, WO2007133828.

In a further embodiment, the compound of the formula I is administeredin combination with an agonist of the endothelin receptor, as described,for example, in WO2007112069.

In a further embodiment, the compound of the formula I is administeredin combination with AKP-020 (bis(ethylmaltolato)oxovanadium(IV)).

In another embodiment, the compound of the formula I is administered incombination with tissue-selective androgen receptor modulators (SARM),as described, for example, in WO2007099200.

In one embodiment of the invention, the further active ingredient isleptin;

see, for example, “Perspectives in the therapeutic use of leptin”,Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinionon Pharmacotherapy (2001), 2(10), 1615-1622.

In another embodiment of the invention, the further active ingredient ismetreleptin (recombinant methionyl-leptin) combined with pramlintide.

In a further embodiment of the invention, the further active ingredientis the tetrapeptide ISF-402.

In one embodiment, the further active ingredient is dexamphetamine oramphetamine.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In one embodiment, the further active ingredient is mazindol orphentermin.

In a further embodiment, the further active ingredient is geniposidicacid (WO2007100104).

In one embodiment, the compound of the formula I is administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, Carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Höchst, 65926 Frankfurt/Main)). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can also beadministered in the form of food products such as, for example, inbakery products or muesli bars.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isconsidered to be covered by the scope of protection conferred by thepresent invention.

EXAMPLES

The examples and preparation methods adduced below serve to illustratethe invention, but without limiting it.

The inventive compounds of the formula I can be prepared with the aid ofreactions known in principle. For example, the compounds were preparedaccording to the general reaction schemes which follow.

A methanesulfonyl chloride substituted by R2 and R3, through thereaction with

a suitable amine and triethylamine, is used to prepare a correspondingR2- and R3-substituted methanesulfonamide protected by R12 (e.g. Boc,benzyl, 2,4-dimethoxybenzyl). By treatment with a suitable base (e.g.methyllithium) at low temperature, it is then possible to produce adianion, which reacts with a ketone or an aldehyde to give theR12-protected hydroxysulfonamide. By deprotection of R12 (for example,by acid treatment in the case of a Boc group or of a 2,4-dimethoxybenzylgroup, or by hydrogenation in the case of a benzyl group), the freehydroxysulfonamide is formed. The treatment of the hydroxysulfonamidewith base and an isothiocyanate, and subsequent oxidative ring closurewith NBS, gives the desired 4,4-dioxooxathiazines.

In the cases in which the functional groups (for example a hydroxylgroup) are introduced in protected form (for example benzyl-protected oras the ester), these are released at the end of the synthesis by asuitable method (for example hydrogenation or reduction).

The isothiocyanates used are obtained by the reaction of a primary aminewith thiocarbonyldiimidazole, in which case any troublesome functionalgroups present, for example hydroxyl groups, are blocked with suitableprotecting groups, for example silyl ethers. The protecting groups areremoved at the end of the sequence by suitable methods, for examplesilyl groups by treatment with methanolic hydrochloric acid.

In the cases in which diastereomers or racemates form during thesynthesis, these can be separated from one another by preparative HPLC.

Some of the primary amines used are commercially available.

4-Fluorobicyclo[2.2.2]octan-1-amine can be prepared as described in theliterature (JOC 1982, 47, 1952-7).

Other inventive compounds can be obtained in other ways outlined by wayof example in the scheme which follows.

In analogy to a literature method (JACS 1972, 94, 4386-7),chlorosulfonyl isocyanate is treated with an alcohol (e.g. methanol),forming a corresponding carboalkoxysulfamoyl chloride (e.g.carbomethoxysulfamoyl chloride). This can be deprotonated with sodiumhydride, and the intermediate formed after chloride elimination (e.g.methyl-N-sulfonylurethane) reacts in a 2+4 cycloaddition with alkenes toform an alkoxy-substituted (e.g. methoxy-substituted)4,4-dioxooxathiazine. The alkoxy group can be replaced here by means ofan amine in a suitable solvent (e.g. dichloromethane), forming thedesired 4,4-dioxooxathiazines.

In the cases in which diastereomers or racemates form during thesynthesis, these can be separated from one another by preparative HPLC.

In the cases in which the functional groups (for example a hydroxylgroup) are introduced in protected form (for example benzyl-protected oras the ester), these are released at the end of the synthesis by asuitable method (for example hydrogenation or reduction).

Some of the amines used are commercially available or can be prepared bymethods known from the literature.

Others among the primary amines used were prepared as outlined in thescheme which follows.

The examples adduced hereinafter serve to illustrate the invention, butwithout restricting it.

TABLE Molecular Exam- Retention weight ple CHEMISTRY Method time (g/mol)Name  1

A 1.233 286.4 Cyclohexyl-(8,8-dimethyl-4,4-dioxo-7-oxa-4lambda6-thia-5-aza-spiro[2.5]oct-5-en-6-yl)- amine  2

C 0.96  288.4 Cyclohexyl-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin- 2-yl)-amine  3

A 1.071 300.4 Cyclohexyl-(11,11-dioxo-6,8-dioxa-11lambda6-thia-10-aza-dispiro[2.0.3.4]undec-9-en-9-yl)- amine  4

A 1.202 316.4 Cyclohexyl-(8-methoxymethyl-8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-aza- spiro[2.5]oct-5-en-6-yl)-amine  5

A 1.02  338.4 (S)-3-(8,8-Dimethyl-4,4-dioxo-7-oxa-4lambda6-thia-5-aza-spiro[2.5]oct-5-en-6- ylamino)-3-phenyl-propan-1-ol 6

A 1.816 392.5 (8-Benzyloxymethyl-8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-aza-spiro[2.5]oct-5-en-6-yl)- cyclohexyl-amine  7

A 1.278 302.4 (6-Cyclohexylamino-8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-aza-spiro[2.5]oct-5-en-8-yl)- methanol  8

A 1.225 330.4 (8,8-Dimethyl-4,4-dioxo-7-oxa-4lambda6-thia-5-aza-spiro[2.5]oct-5-en-6-yl)-(4-fluoro- bicyclo[2.2.2]oct-1-yl)-amine 9

C 0.95  332.4 (4-Fluoro-bicyclo[2.2.2]oct-1-yl)-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)-amine 10

C 0.847 340.4 (S)-3-Phenyl-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2- ylamino)-propan-1-ol 11

C 0.902 374.9 (S)-3-(2-Chloro-phenyl)-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)-propan-1-ol 12

C 0.875 358.4 (S)-3-(4-Fluoro-phenyl)-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)-propan-1-ol 13

C 1.05  340.4 Cyclohexyl-(8-methyl-4,4-dioxo-8-trifluoromethyl-7-oxa-4lambda6-thia-5-aza-spiro[2.5]oct-5-en-6-yl)-amine 14

B 0.696 407.5 (R)-2-(4-Fluoro-phenyl)-2-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6- [1,4,3]oxathiazin-2-ylamino)-ethanesulfonamide 15

C 1.025 314.4 Bicyclo[2.2.2]oct-1-yl-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6- [1,4,3]oxathiazin-2-yl)-amine 16

C 0.355 369.5 (S)-2-Methyl-4-pyridin-3-yl-4-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)-butan- 2-ol 18

C 0.709 304.4 (1S,3S)-3-(5,5,6,6-Tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2- ylamino)-cyclohexanol 20

C 0.963 310.4 ((S)-1-Phenyl-ethyl)-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6- [1,4,3]oxathiazin-2-yl)-amine 21

C 0.978 328.4 [(S)-1-(2-Fluoro-phenyl)-ethyl]-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)-amine 22

C 0.823 365.4 3-[(S)-3-Hydroxy-1-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6- [1,4,3]oxathiazin-2-ylamino)-propyl]-benzonitrile 23

C 0.991 402.9 (S)-4-(2-Chloro-phenyl)-2-methyl-4-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)-butan- 2-ol 24

C 1.024 344.9 [(S)-1-(2-Chloro-phenyl)-ethyl]-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)-amine 25

C 0.714 304.4 (1R,3R)-3-(5,5,6,6-Tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2- ylamino)-cyclohexanol 26

A 1.276 298.4 Cyclohexyl-(11,11-dioxo-8-oxa-11lambda6-thia-10-aza-dispiro[2.0.3.4]undec-9-en-9-yl)- amineChromatography Methods:Method A

Column: YMC J'spere ODS H80, 80 {acute over (Å)}, S-4 μm, 20×2.1 mm

Eluent: 0 min 96% H₂O (0.05% TFA)—2.0 min 95% acetonitrile—2.4 min 95%acetonitrile—2.45 min 4% acetonitrile (30° C., flow rate 1 ml/min)

Method B

Column: Mercury MS, Luna C18(2), S-3 μm, 10×2.0 mm

Eluent: 0 min 93% H₂O (0.05% TFA)—1.2 min 95% acetonitrile—1.4 min 95%acetonitrile—1.45 min 7% acetonitrile (30° C., flow rate 1.1 ml/min)

Method C

Column: Mercury MS, Luna C18(2), S-3 μm, 10×2.0 mm

Eluent: 0 min 93% H₂O (0.05% TFA)—1.0 min 95% acetonitrile—1.45 min 95%acetonitrile—1.5 min 7% acetonitrile (30° C., flow rate 1.1 ml/min)

The efficacy of the compounds was tested as follows:

Enzymatic 11beta-HSD1 Test:

To measure the activity of the compounds, an SPA-based detection method(Solly et al. 2005) was employed. First of all, 20 μl of the human11β-HSD1 microsome fraction (0.2 μg of protein), prepared in 50 mMHEPES, 0.1% BSA (w/v), were applied to a plate with 384 wells. The testcompounds (0.09 μl) were applied to the assay plate in 100% DMSO. Thereaction was started by addition of 20 μl of [1,2-³H]-cortisone (0.1μCi/100 mM) in assay buffer comprising 25 mM HEPES, 100 mM KCl, 5 mMNaCl, 2 mM MgCl₂ and 0.25 mM NADPH. The plate was agitated at 37° C. for1 hour. At the same time, a stop solution comprising 20 mg/ml SPA-PVTbeads, 1.6 mg/ml monoclonal cortisol antibody and 0.01 mM SSR110887(inhibitor from the Biovitrium patent) in 50 mM HEPES, 1 M NaCl and 1 MKCl was stirred at room temperature. To stop the reaction, 25 μl of thestop solution were added to each well. The plate was agitated gently atroom temperature for 1 further hour and then centrifuged at 500 g_(av)for 1 min, in order that the SPA beads could settle out. The plate wasthen read in a Wallac-1450-Microbeta unit with a standard SPA program(counting time 1 min/well). The comparative compound was glycyrrhetinicacid.

Protein and radioactive substrate were dispensed with a Biomek FX unit(Beckman Coulter) for handling liquids. The test compounds were addedwith a Cybi-Well equipped with a 90 n1 pin tool (CyBio).

Lit.: Solly S, Mundt S S, Zokian H J, Juy-Fang Ding G,Hermanowski-Vosatka A, Strulovici B and Zheng W. High-throughputscreening of 11β-Hydroxysteroid dehydrogenase type 1 in scintillationproximity format. Assay Drug Dev Technol 2005; 3:377-384.

TABLE 2 Biological activity in nanomolar (nM) Example IC₅₀ (nM) 1 28 218 3 139 4 462 5 37 6 73 7 786 8 22 9 4 10 7 11 4 12 7 13 19 14 10 15 416 586 18 560 20 15 21 5 22 6 23 11 24 4 25 289 26 82

It can be inferred from the test data that the compounds of the formulaI inhibit 11beta-HSD1 (11beta-hydroxysteroid dehydrogenase type 1), andare thus of good suitability for treatment of hyperglycemia, insulinresistance, diabetes, obesity, lipid metabolism disorders, high bloodpressure, cognitive improvement, elevated intraocular pressure,promotion of wound healing, and other diseases.

The preparation of some examples is described in detail hereinafter; theremaining compounds of the formula I were obtained analogously:

ExperimentalCyclohexyl-(4,4-dioxo-8-phenyl-7-oxa-4lambda*6*-thia-5-azaspiro[2.5]oct-5-en-6-yl)amine

Cyclopropanesulfonamide

A mixture of 50 ml of 25% aqueous ammonia solution and 50 ml of THF wasinitially charged, and then 10.00 g of cyclopropanesulfonyl chloride in10 ml of THF were slowly added dropwise and the mixture was stirred for16 hours. After concentration by rotary evaporation and coevaporationwith toluene, the residue was extracted by stirring with 100 ml of ethylacetate and the solids were filtered off. The organic phase was driedover Na₂SO₄ and concentrated by rotary evaporation. This gave theproduct (7.03 g) with a molecular weight of 121.2 g/mol (C₃H₇NO₂S); MS(ESI): m/e=122 (M+H⁺).

N-tert-Butyloxycarbonylcyclopropanesulfonamide

1.46 g of cyclopropanesulfonamide were initially charged in a mixture of30 ml of dichloromethane and 1.67 ml of triethylamine, and then 2.63 gof di-tert-butyl dicarbonate and 0.15 g of 4-dimethylaminopyridine wereadded and the mixture was stirred for 16 hours. The reaction solutionwas washed with 1 N aqueous hydrochloric acid, saturated aqueous sodiumchloride solution and water, and the organic phase was dried over Na₂SO₄and concentrated by rotary evaporation. This gave the product (2.66 g)with a molecular weight of 221.3 g/mol (C₈H₁₅NO₄S); MS (EST): m/e=166(M-tert-Butyl+H⁺).

N-tert-Butyloxycarbonyl-1-(hydroxyphenylmethyl)cyclopropansulfonamide

Under inert gas, 1.00 g ofN-tert-butyloxycarbonylcyclopropanesulfonamide were initially charged in40 ml of THF, and then, at a temperature of −78° C., 6.63 ml of a 1.5 Nbutyllithium solution in hexane were added dropwise and the mixture wasleft to stir while cooling with ice for 1 hour. After stirring at roomtemperature for a further 30 minutes, the mixture was cooled again to−78° C., and a solution of 0.92 ml of benzaldehyde in 4 ml of THF wasadded. The mixture was allowed to come to room temperature whilestirring overnight. The reaction solution was diluted with 20 ml of asaturated aqueous ammonium chloride solution and extracted with 40 ml ofethyl acetate, and the organic phase was dried over Na₂SO₄ andconcentrated by rotary evaporation. The crude product was purified bymeans of normal phase chromatography using a Flashmaster with ann-heptane/ethyl acetate gradient. The product-containing fractions werecombined and concentrated by rotary evaporation. This gave the product(880 mg) with a molecular weight of 327.4 g/mol (C₁₅H₂₁NO₅S); MS (ESI):m/e=254 (M-tert-butanol+H⁺).

1-(Hydroxyphenylmethyl)cyclopropanesulfonamide

880 mg ofN-tert-butyloxycarbonyl-1-(hydroxyphenylmethyl)cyclopropanesulfonamidewere dissolved in 25 ml of ethyl acetate, and 13.4 ml of a 1 N aqueoushydrochloric acid were added. The reaction solution was heated to 65° C.and the completeness of the conversion was checked with LCMS. After 8hours, the mixture was neutralized with saturated aqueous sodiumcarbonate solution, and the organic phase was dried over Na₂SO₄ andconcentrated by rotary evaporation. This gave the product (610 mg) witha molecular weight of 227.3 g/mol (C₁₀H₁₃NO₃S); MS (ESI): m/e=210(M−H₂O+H⁺).

Cyclohexyl-(4,4-dioxo-8-phenyl-7-oxa-4lambda*6*-thia-5-azaspiro[2.5]oct-5-en-6-yl)amine

610 mg of 1-(hydroxyphenylmethyl)cyclopropanesulfonamide were dissolvedin 5 ml of NMP and then stirred with 331 mg of potassium tert-butoxidefor 5 minutes. Then 569 mg of cyclohexyl isothiocyanate were added.After stirring for 15 minutes, 525 mg of N-bromosuccinimide were thenadded and the mixture was stirred for a further 90 minutes. The solutionwas purified by preparative HPLC. This gave the product (191 mg) with amolecular weight of 334.4 g/mol (C₁₇H₂₂N₂O₃S); MS (ESI): m/e=335 (M+H⁺).

Compounds 1, 3-6, 8, 9, 17, 18, 20 and 40 were synthesized by thispreparation method:

-   Cyclohexyl-(8,8-dimethyl-4,4-dioxo-7-oxa-4-lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)-amine-   Cyclohexyl-(8-ethyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)amine-   Cyclohexyl-(8-isopropyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)amine-   Cyclohexyl-(4,4-dioxo-8-propyl-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)amine-   (8-tert-Butyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)cyclohexylamine-   Cyclohexyl-(8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)amine-   Cyclohexyl-(5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)amine-   Cyclohexyl-(11,11-dioxo-6,8-dioxa-11lambda6-thia-10-aza-dispiro[2.0.3.4]undec-9-en-9-yl)amine-   Cyclohexyl-(8-methoxymethyl-8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)amine-   (8-Benzyloxymethyl-8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)-cyclohexylamine-   Cyclohexyl-(11,11-dioxo-8-oxa-11lambda6-thia-10-aza-dispiro[2.0.3.4]undec-9-en-9-yl)amine-   (6-Cyclohexylamino-8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-8-yl)methanol

Under inert gas, 80 mg of(8-benzyloxymethyl-8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)cyclohexylaminewere initially charged in 6 ml of ethanol and, with addition of 5 mg of5% Pd/C, stirred under a hydrogen atmosphere for 16 hours. Thecompleteness of the conversion was checked by LCMS and the reaction wasonce again admixed with 5 mg of 5% Pd/C, and the mixture was stirredunder a hydrogen atmosphere for a further 2 hours. After filtration toremove the solid residues, the filtrate was freed of the solvent underreduced pressure. The crude product was purified by means of normalphase chromatography using a Flashmaster with an n-heptane/ethyl acetategradient. The product-containing fractions were combined andconcentrated by rotary evaporation, then taken up again in 10 ml of amixture of acetonitrile and water (9:1) and lyophilized. This gave theproduct (32 mg) with a molecular weight of 302.4 g/mol (C₁₃H₂₂N₂O₄S); MS(ESI): m/e=303 (M+H⁺).

Cyclohexyl-(8-methyl-4,4-dioxo-8-trifluormethyl-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)amine

The preparation was effected analogously to the above-describedsynthesis of compound 2. The introduction of the additional methyl groupis described hereinafter.

1-(2,2,2-Trifluoro-1-hydroxy-1-methylethyl)cyclopropanesulfonamide

Under inert gas, 250 mg of1-(2,2,2-trifluoroacetyl)cyclopropanesulfonamide were initially chargedin 6 ml of THF and then, at a temperature of −78° C., 1.15 ml of a 3.0 Nmethylmagnesium bromide solution in diethyl ether were added dropwiseand the mixture was stirred at constant temperature for 4 hours. Thereaction solution was admixed with 5 ml of a saturated aqueous ammoniumchloride solution and allowed to come to room temperature whilestirring. After adjustment to pH 5 with 2 N aqueous hydrochloric acid,the mixture was extracted with 10 ml of ethyl acetate, and the organicphase was dried over Na₂SO₄ and concentrated by rotary evaporation. Thisgave the product (208 mg) with a molecular weight of 233.2 g/mol(C₆H₁₀F₃NO₃S); MS (ESI): m/e=234 (M+H⁺).

(8,8-Dimethyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)-(4-fluorobicyclo[2.2.2]oct-1-yl)amine

The amine used was prepared as follows:

Amino-4-fluorobicyclo[2.2.2]octane

Journal of Organic Chemistry 1982, 47(15), 2951-2957.

157 mg of 4-fluorobicyclo[2.2.2]oct-1-ylamine hydrochloride wereinitially charged in 2 ml of dichloromethane, and then 174 mg of1,1′-thiocarbonyldiimidazole and 0.172 ml of triethylamine were added.After stirring at room temperature for 30 minutes, the batch was admixedwith a mixture of 10 ml of diethyl ether and 10 ml of n-pentane, andwashed with water. The organic phase was dried over MgSO₄ andconcentrated by rotary evaporation, and the residue was dissolved in 1.5ml of NMP. This solution was added to a suspension of 146 mg of1-(1-hydroxy-1-methylethyl)cyclopropanesulfonamide and 101 mg ofpotassium tert-butoxide in 1.5 ml of NMP. After stirring for 1 hour, 149mg of N-bromosuccinimide were added and the resulting reaction solutionwas stirred again for 1 hour. The reaction mixture was admixed with 40ml of water and extracted three times with 15 ml of ethyl acetate. Thecombined organic phases were washed with 1 N aqueous potassiumhydrogensulfate solution and twice with saturated aqueous sodiumchloride solution, dried over MgSO₄ and concentrated by rotaryevaporation. The residue was purified in a purification laboratory bymeans of preparative HPLC, and the product-containing fractions werelyophilized. This gave the product (9.1 mg) with a molecular weight of330.4 g/mol (C₁₅H₂₃FN₂O₃S); MS (ESI): m/e=331 (M+H⁺).

(S)-3-(8,8-Dimethyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-ylamino)-3-phenylpropan-1-ol

232 mg of (S)-3-amino-3-phenylpropan-1-ol were initially charged in 5 mlof dichloromethane and then 0.58 ml of triethylamine and 231 mg oftert-butyldimethylchlorosilane were added. The reaction solution wasstirred at room temperature and the progress of the conversion wasmonitored by LCMS. After 1 hour, a further 42 mg oftert-butyldimethylchlorosilane were added and the mixture was stirredfor 64 hours. Subsequently, the reaction solution was added to 10 ml ofwater and extracted with a mixture of 10 ml of diethyl ether and 10 mlof n-pentane. After drying over Na₂SO₄ and concentrating by rotaryevaporation, the residue was dissolved in 5 ml of dichloromethane, and274 mg of 1,1′-thiocarbonyldiimidazole were added and the mixture wasstirred for 30 minutes. The reaction solution was washed 2× with 5 ml ofwater, dried over Na₂SO₄ and concentrated by rotary evaporation, and theresidue was dissolved in 2 ml of NMP.

250 mg of 1-(1-hydroxy-1-methylethyl)cyclopropanesulfonamide wasdissolved in 2 ml of NMP, and admixed while cooling with ice with 0.70ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF and,after stirring for 5 minutes, with the isothiocyanate solution preparedabove. After stirring for 1.5 hours, 248 mg of N-bromosuccinimide wereadded and the resulting reaction solution was stirred again for 10minutes. The reaction mixture was added to 20 ml of water and extractedthree times with 20 ml of ethyl acetate. The combined organic phaseswere dried with saturated aqueous sodium chloride solution, dried overNa₂SO₄ and concentrated by rotary evaporation. The residue was dissolvedin 5 ml of methanol, 0.20 ml of concentrated hydrochloric acid was addedand the mixture was stirred for 1.5 hours. After the addition of 1.26 mlof 1 N aqueous sodium hydroxide solution, the mixture was concentratedby rotary evaporation and purified in a purification laboratory by meansof preparative HPLC. After lyophilization of the product-containingfractions, the product (26 mg) was thus obtained with a molecular weightof 338.4 g/mol (C₁₆H₂₂N₂O₄S); MS (ESI): m/e=339 (M+H⁺).

Cyclohexyl-(8,8-dioxo-5-oxa-8lambda6-thia-7-azaspiro[3.5]non-6-en-6-yl)amine

N-Benzylmethanesulfonamide

18.27 g of benzylamine were dissolved in 100 ml of methylene chlorideand, while cooling with ice, 6.00 ml of methanesulfonyl chloride werevery slowly added dropwise. On completion of addition of themethanesulfonyl chloride, the reaction solution was diluted with 100 mlof water, and the aqueous phase was extracted again with 50 ml ofmethylene chloride. The combined organic phases were washed with 1 Naqueous hydrochloric acid, dried over MgSO₄ and concentrated by rotaryevaporation. This gave the product (14.40 g) with a molecular weight of185.3 g/mol (C₈H₁₁NO₂S).

(1-Hydroxycyclobutyl)methanesulfonamide

Under inert gas, 2.00 g of N-benzylmethanesulfonamide were initiallycharged in 20 ml of THF, then, at a temperature of −78° C., 13.50 ml ofa 1.6 N solution of butyllithium in hexane were added dropwise and themixture was stirred at constant temperature for 5 minutes. The reactionsolution was admixed with 3.23 ml of cyclobutanone and allowed to cometo room temperature while stirring. After the addition of 1.24 ml ofacetic acid, the volatile constituents were removed under reducedpressure. The residue was taken up in a mixture of 50 ml of ethylacetate and 50 ml of aqueous sodium hydrogencarbonate solution, and theaqueous phase was extracted again with 50 ml of ethyl acetate. Thecombined organic phases were dried over MgSO₄ and concentrated by rotaryevaporation. The crude product thus obtained was recrystallized fromethyl acetate/n-heptane, then dissolved in 20 ml of methanol and, withaddition of 0.36 g of 20% Pd(OH)₂/C, stirred under a hydrogen atmosphereat 60° C. for 3 hours. After filtration to remove the solid residues,the filtrate was freed of the solvent under reduced pressure. This gavethe product (1.07 g) with a molecular weight of 165.2 g/mol (C₅H₁₁NO₃S).

Cyclohexyl-(8,8-dioxo-5-oxa-8lambda*6*-thia-7-azaspiro[3.5]non-6-en-6-yl)amine

Under inert gas, 200 mg of (1-hydroxycyclobutyl)methanesulfonamide weredissolved in 2.5 ml of NMP, and admixed at −10° C. with 0.61 ml of a 2 Nsolution of sodium bis(trimethylsilyl)amide in THF and, after stirringfor 5 minutes, with a solution of 0.19 ml of cyclohexyl isothiocyanatein 0.5 ml of NMP. After stirring at constant temperature for 40 minutes,215 mg of N-bromosuccinimide were added in 4 portions within 5 minutes,and the reaction solution was stirred for a further 15 minutes. Thereaction mixture was diluted with 60 ml of water and extracted twicewith 20 ml of ethyl acetate. The combined organic phases were washedwith saturated aqueous sodium chloride solution, dried over MgSO₄ andconcentrated by rotary evaporation. The residue was purified in apurification laboratory by means of preparative HPLC. Afterlyophilization of the product-containing fractions, the product (114.7mg) was thus obtained with a molecular weight of 272.4 g/mol(C₁₂H₂₀N₂O₃S); MS (ESI): m/e=273 (M+H⁺).

Compounds 11 and 12 were synthesized by this preparation method:

-   Cyclohexyl-(9,9-dioxo-6-oxa-9lambda6-thia-8-azaspiro[4.5]dec-7-en-7-yl)amine-   Cyclohexyl-(4,4-dioxo-1-oxa-4lambda6-thia-3-azaspiro[5.5]undec-2-en-2-yl)amine

(S)-3-(8,8-Dioxo-5-oxa-8lambda6-thia-7-azaspiro[3.5]non-6-en-6-ylamino)-3-phenylpropan-1-ol

The preparation was effected analogously to the above-describedsynthesis of compound 10. The introduction of the amino alcohol isdescribed hereinafter.

(S)-3-(tert-Butyldimethylsilanyloxy)-1-phenylpropylamine

1.50 g of (S)-3-amino-3-phenylpropan-1-ol hydrochloride were initiallycharged in 20 ml of dichloromethane and then 2.77 ml of triethylamineand 1.30 g of tert-butyldimethylchlorosilane were added. After stirringat room temperature for 3 hours, the reaction solution was extractedthree times with 30 ml of water, dried by means of a phase separatorcartridge (Isolute®), concentrated by rotary evaporation and dried underhigh vacuum. This gave the product (2.06 g) with a molecular weight of265.5 g/mol (C₁₅H₂₇NOSi); MS (ESI): m/e=266 (M+H+).

(S)-3-(8,8-Dioxo-5-oxa-8lambda6-thia-7-azaspiro[3.5]non-6-en-6-ylamimo)-3-phenylpropan-1-ol

345 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropylamine weredissolved in 3 ml of dichloromethane, 256 mg of1,1′-thiocarbonyldiimidazole were added and the mixture was stirred for20 minutes. The reaction solution was admixed with a mixture of 20 ml ofdiethyl ether and 20 ml of n-pentane, and washed three times with 30 mlof water, dried over MgSO₄ and concentrated by rotary evaporation, andthe residue was dissolved in 1 ml of NMP. Under inert gas, 192 mg of(1-hydroxycyclobutyl)methanesulfonamide were dissolved in 1.5 ml of NMP,and admixed at −10° C. with 0.58 ml of a 2 N solution of sodiumbis(trimethylsilyl)amide in THF and, after stirring for 5 minutes, withthe isothiocyanate solution prepared above. After stirring for 30minutes, 207 mg of N-bromosuccinimide were added in 4 portions and theresulting reaction solution was stirred at constant temperature for 30minutes. The reaction mixture was diluted with 50 ml of water andextracted twice with 20 ml of ethyl acetate. The combined organic phaseswere washed with 20 ml of saturated aqueous ammonium chloride solution,dried over MgSO₄ and concentrated by rotary evaporation. The residue wasdissolved in 3 ml of methanol, 0.30 ml of concentrated hydrochloric acidwas added and the mixture was stirred for 1.5 hours. The reactionsolution was admixed with 15 ml of water and ethyl acetate, the organicphase was dried over MgSO₄ and concentrated by rotary evaporation, andthe residue was purified in a purification laboratory by means ofpreparative HPLC. The product-containing fractions were combined andfreed of the solvent under reduced pressure, and the aqueous residue waslyophilized. To cleave the ethyl trifluoroacetate which had formed aspart of the products, the lyophilizate was dissolved again in methanol,0.5 ml of a 4 N solution of hydrochloric acid in dioxane was added andthe mixture was stirred at room temperature for 6 hours. The solutionwas admixed with 10 ml of acetonitrile and concentrated by rotaryevaporation, and the residue was dissolved in a little acetonitrile,water was added and the mixture was lyophilized. This gave the product(187.4 mg) with a molecular weight of 324.4 g/mol (C₁₅H₂₀N₂O₄S); MS(ESI): m/e=325 (M+H⁺).

Compounds 13, 15 and 16 were synthesized by this preparation method:

-   (S)-3-(6,6-Dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)-3-phenylpropan-1-ol-   (S)-3-(9,9-Dioxo-6-oxa-9lambda6-thia-8-azaspiro[4.5]dec-7-en-7-ylamino)-3-phenylpropan-1-ol-   (S)-3-(4,4-Dioxo-1-oxa-4lambda6-thia-3-azaspiro[5.5]undec-2-en-2-ylamino)-3-phenylpropan-1-ol

Cyclohexyl-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)amine

5,5,6,6-Tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide

7.40 g of chlorosulfonyl isocyanate and 7.27 g of 4-nitrophenol weredissolved in 75 ml of dichloromethane and stirred at room temperaturefor 90 minutes. The reaction solution was freed of the solvent underreduced pressure, and the residue was dissolved in 50 ml of THF and,under inert gas and at −78° C., admixed with 2.18 g of sodium hydride.After stirring for 5 minutes, 4.38 g of 2,3-dimethyl-2-butene were addedand the reaction mixture was heated, gradually because of commencementof evolution of gas, to 35° C. After stirring for 30 minutes, thesuspension was added to ice and the resulting THF/water mixture wasextracted twice with 100 ml of ethyl acetate. The combined organicphases were dried over Na₂SO₄ and concentrated by rotary evaporation.The residue was purified in a purification laboratory by means ofpreparative HPLC. After lyophilization of the product-containingfractions, the product (2.76 g) was thus obtained with a molecularweight of 328.4 g/mol (C₁₃H₁₆N₂O₆S).

Cyclohexyl-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)amine

200 mg of5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 60 mg of cyclohexylamine were dissolved in 2 ml ofdichloromethane, and the mixture was stirred at room temperature for 15minutes. Subsequently, the reaction solution was diluted with 50 ml ofdichloromethane, washed twice with 50 ml of 0.1 N aqueous sodiumhydroxide solution, twice with 50 ml of 1 N aqueous hydrochloric acidand with 50 ml of saturated aqueous sodium hydrogencarbonate solution,dried over Na₂SO₄ and concentrated by rotary evaporation. This gave theproduct (41 mg) with a molecular weight of 288.4 g/mol (C₁₃H₂₄N₂O₃S); MS(ESI): m/e=289 (M+H⁺).

Bicyclo[2.2.2]oct-1-yl-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)amine

The amine used was prepared as follows:

1-Aminobicyclo[2.2.2]octane

Helvetica Chimica Acta 1964, 47(2), 564-567.

300 mg of5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 163 mg of 1-aminobicyclo[2.2.2]octane hydrochloride weredissolved in a mixture of 5 ml of dichloromethane and 0.38 ml ofN,N-diisopropylethylamine, and the mixture was stirred at roomtemperature for 72 hours. Subsequently, the reaction solution wasconcentrated by rotary evaporation and the residue was purified in apurification laboratory by means of preparative HPLC. Afterlyophilization of the product-containing fractions, the product (166 mg)was thus obtained with a molecular weight of 314.5 g/mol (C₁₅H₂₆N₂O₃S);MS (ESI): m/e=315 (M+H⁺).

[(S)-1-(2-Fluorophenyl)ethyl]-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)amine

200 mg of5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 111 mg of (S)-1-(2-fluorophenyl)ethylamine weredissolved in 1 ml of dichloromethane and 0.10 ml ofN,N-diisopropylethylamine, and the mixture was stirred at roomtemperature for 16 hours. Subsequently, the reaction solution wasdiluted with 50 ml of dichloromethane, washed three times with 30 ml of10% aqueous ammonia solution, three times with 30 ml of 1 N aqueoushydrochloric acid and with 30 ml of saturated aqueous sodiumhydrogencarbonate solution, dried over Na₂SO₄ and concentrated by rotaryevaporation. This gave the product (194 mg) with a molecular weight of328.4 g/mol (C₁₅H₂₁FN₂O₃S); MS (ESI): m/e=329 (M+H⁺).

3-[(S)-3-Hydroxy-1-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)propyl]benzonitrile

N-[3-(tert-Butyldimethylsilanyloxy)prop-(E)-ylidene]-(S_(S))-2-methylpropane-2-sulfinamide

Under inert gas, 2.83 g of (S)-(−)-2-methylpropane-2-sulfinamide wereinitially charged 60 ml of dichloromethane and, with addition of 4.00 gof 3-(tert-butyldimethylsilanyloxy)propionaldehyde and 8.48 g ofanhydrous copper sulfate, stirred at room temperature for 16 hours. Thecompleteness of the conversion was checked by LCMS and the reaction wasstirred for a further 24 hours. After filtration to remove the solidresidues, the filtrate was freed of the solvent under reduced pressure.The crude product was purified by means of normal phase chromatographyusing a Flashmaster with an n-heptane/ethyl acetate gradient. Theproduct-containing fractions were combined and concentrated by rotaryevaporation. This gave the product (5.03 g) with a molecular weight of291.5 g/mol (C₁₃H₂₉NO₂SSi); MS (ESI): m/e=292 (M+H⁺).

N—[(S)-3-(tert-Butyldimethylsilanyloxy)-1-(3-cyanophenyl)propyl]-(S_(S))-2-methylpropane-2-sulfinamide

A flask which had been baked out under inert gas was initially chargedwith 9.73 ml of a 14% solution of the isopropylmagnesiumchloride/lithium chloride complex in THF (d=0.951 g/ml) and cooled to−15° C. After the addition of a solution of 1.56 g of3-bromobenzonitrile in 5 ml of THF, the mixture was allowed to warm upto a temperature of −5° C. within 30 minutes. In a further flask whichhad been baked out under inert gas, 1.00 g ofN-[3-(tert-butyldimethylsilanyloxy)prop-(E)-ylidene]-(S_(S))-2-methylpropane-2-sulfinamidewas dissolved in 50 ml of toluene and, at a temperature of −78° C., thesolution from the first flask was added dropwise. The reaction solutionwas stirred for 16 hours and, during this time, allowed to come to roomtemperature. Subsequently, the reaction solution was admixed with 5 mlof saturated aqueous ammonium chloride solution and freed of the solventunder reduced pressure. The residue was taken up in 50 ml of water and50 ml of ethyl acetate, and the organic phase was dried over Na₂SO₄ andconcentrated by rotary evaporation. The crude product was purified bymeans of normal phase chromatography using a Flashmaster with ann-heptane/ethyl acetate gradient. The product-containing fractions werecombined and concentrated by rotary evaporation. This gave the product(0.25 g) with a molecular weight of 394.7 g/mol (C₂₀H₃₄N₂O₂SSi); MS(ESI): m/e=395 (M+H⁺).

3-((S)-1-Amino-3-hydroxypropyl)benzonitrile hydrochloride

430 mg ofN—[(S)-3-(tert-butyldimethylsilanyloxy)-1-(3-cyanophenyl)propyl]-(S_(S))-2-methylpropane-2-sulfinamidewere dissolved in 5 ml of methanol and, after addition of 1.36 ml of a 4N hydrochloric acid in dioxane, stirred at room temperature for 1 hour.The solvent was removed under reduced pressure and the crude product wasused in the next reaction without further purification. Thehydrochloride of the product was obtained with a molecular weight of176.2 g/mol (C₁₀H₁₂N₂O); MS (ESI): m/e=177 (M+H⁺).

3-[(S)-3-Hydroxy-1-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)propyl]benzonitrile

100 mg of5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 97 mg of 3-((S)-1-amino-3-hydroxypropyl)benzonitrilehydrochloride were dissolved in 5 ml of dichloromethane and 0.25 ml ofN,N-diisopropylethylamine, and the mixture was stirred at roomtemperature for 16 hours. Subsequently, the reaction solution wasdiluted with 20 ml of dichloromethane, and washed with 10 ml of 10%aqueous ammonia solution and with 10 ml of 1 N aqueous hydrochloricacid. The two aqueous phases were extracted once again with 20 ml ofethyl acetate, and the combined organic phases were dried over Na₂SO₄and concentrated by rotary evaporation. The residue was purified in apurification laboratory by means of preparative HPLC. Afterlyophilization of the product-containing fractions, the product (66 mg)was thus obtained with a molecular weight of 365.5 g/mol (C₁₇H₂₃N₃O₄S);MS (ESI): m/e=366 (M+H+).

The synthesis was performed in analogy to the chiral syntheses describedin the literature. The enantiomeric ratio of the product is 95:5. It isassumed that the S enantiomer has formed in excess.

Tetrahedron 1999, 8883

Journal of Organic Chemistry 2001, 8772

Tetrahedron Letters 2001, 2051

(S)-4-(2-Chlorophenyl)-2-methyl-4-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)butan-2-ol

(S)-3-(2-Chlorophenyl)-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-1,4,3-oxathiazin-2-ylamino)propionicacid methyl ester

200 mg of5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 130 mg of methyl(S)-3-amino-3-(2-chlorophenyl)propionate were dissolved in 5 ml ofdichloromethane and 0.52 ml of N,N-diisopropylethylamine, and themixture was stirred at room temperature for 16 hours. Subsequently, thereaction solution was diluted with 20 ml of dichloromethane and washedrepeatedly with 20 ml of 25% aqueous ammonia solution, until the organicphase was colorless. The organic phase was dried over Na₂SO₄ andconcentrated by rotary evaporation. This gave the product (191 mg) witha molecular weight of 402.9 g/mol (C₁₇H₂₃ClN₂O₅S); MS (ESI): m/e=403(M+H⁺).

(S)-4-(2-Chlorophenyl)-2-methyl-4-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)butan-2-ol

Under inert gas, 191 mg of(S)-3-(2-chlorophenyl)-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-1,4,3-oxathiazin-2-ylamino)propionicacid methyl ester were dissolved in 4 ml of THF, and 0.66 ml of a 3 Nsolution of methylmagnesium bromide in diethyl ether was added. Afterstirring at room temperature for 30 minutes, the reaction solution wasconcentrated by rotary evaporation and the residue was purified in apurification laboratory by means of preparative HPLC. Afterlyophilization of the product-containing fractions, the product (35 mg)was thus obtained with a molecular weight of 402.9 g/mol(C₁₈H₂₇ClN₂O₄S); MS (EST): m/e=403 (M+H+).

[(S)-1-(2-Chlorophenyl)ethyl]-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)amine

Under inert gas, 200 mg of5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 176 mg of (S)-1-(2-chlorophenyl)ethylamine hydrochloridewere dissolved in 1 ml of dichloromethane and 0.21 ml ofN,N-diisopropylethylamine, and the mixture was stirred at roomtemperature for 16 hours. Subsequently, the reaction solution wasdiluted with 50 ml of dichloromethane, washed three times with 30 ml of10% aqueous ammonia solution, three times with 30 ml of 1 N aqueoushydrochloric acid and with 30 ml of saturated aqueous sodiumhydrogencarbonate solution, dried over Na₂SO₄ and concentrated by rotaryevaporation. This gave the product (171 mg) with a molecular weight of344.94 g/mol (C₁₅H₂₁ClN₂O₃S); MS (ESI): m/e=345 (M+H⁺).

(1R,3R)-3-(5,5,6,6-Tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)cyclohexanol

The amine used was prepared as follows:

(1R,3R)-3-Aminocyclohexanol

P. Bernardelli, M. Bladon, E. Lorthiois, A. C. Manage, F. Vernige, R.Wrigglesworth, Tetrahedron: Asymmetry 15 2004, 1451-1455

L. M. Levy, G. de Gonzalo, V. Gotor, Tetrahedron: Asymmetry 15 2004,2051-2056

While cooling with ice, 200 mg of5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 88 mg of (1R,3R)-3-aminocyclohexanol were dissolved in 3ml of dichloromethane and 0.26 ml of N,N-diisopropylethylamine, and themixture was stirred at room temperature for 1.5 hours. Subsequently, thereaction solution was concentrated by rotary evaporation and the residuewas purified in a purification laboratory by means of preparative HPLC.After lyophilization of the product-containing fractions, the product(136 mg) was thus obtained with a molecular weight of 304.4 g/mol(C₁₃H₂₄N₂O₄S); MS (ESI): m/e=305 (M+H⁺).

(4-Fluorobicyclo[2.2.2]oct-1-yl)-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)amine

The reactant,2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide, was synthesized analogously to the already describedpreparation of5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide.

The amine used was prepared as follows:

Amino-4-fluorobicyclo[2.2.2]octane

Journal of Organic Chemistry 1982, 47(15), 2951-2957.

120 mg of2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 67 mg of amino-4-fluorobicyclo[2.2.2]octane weredissolved in 2 ml of dichloromethane and 0.13 ml ofN,N-diisopropylethylamine, and the mixture was stirred at roomtemperature for 15 minutes. Subsequently, the reaction solution wasdiluted with 50 ml of dichloromethane, washed twice with 50 ml of 0.1 Naqueous sodium hydroxide solution, twice with 50 ml of 1 N aqueoushydrochloric acid and with 50 ml of saturated aqueous sodiumhydrogencarbonate solution, dried over Na₂SO₄ and concentrated by rotaryevaporation. The residue was purified in a purification laboratory bymeans of preparative HPLC. After lyophilization of theproduct-containing fractions, the product (12.1 mg) was thus obtainedwith a molecular weight of 332.4 g/mol (C₁₅H₂₅FN₂O₃S); MS (ESI): m/e=333(M+H+).

Compounds 24-26 were synthesized by this preparation method:

-   (S)-3-Phenyl-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)propan-1-ol-   (S)-3-(2-Chlorophenyl)-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)propan-1-ol-   (S)-3-(4-Fluorophenyl)-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)propan-1-ol

(S)-2-Methyl-4-pyridin-3-yl-4-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)butan-2-ol

(S)-3-Pyridin-3-yl-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-1,4,3-oxathiazin-2-ylamino)propionicacid methyl ester trifluoroacetate

195 mg of2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 132 mg of methyl (S)-3-amino-3-pyridin-3-ylpropionatewere dissolved in 2 ml of dichloromethane and 0.26 ml ofN,N-diisopropylethylamine, and the mixture was stirred at roomtemperature for 48 hours. After concentration by rotary evaporation, theresidue was purified in a purification laboratory by means ofpreparative HPLC. After lyophilization of the product-containingfractions, the trifluoroacetate of the product (97.4 mg) was thusobtained with a molecular weight of 369.4 g/mol (C₁₆H₂₃N₃O₅S); MS (ESI):m/e=370 (M+H⁺).

(S)-2-Methyl-4-pyridin-3-yl-4-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)butan-2-ol

Under inert gas, 50 mg of(S)-3-pyridin-3-yl-3-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-1,4,3-oxathiazin-2-ylamino)propionicacid methyl ester trifluoroacetate were dissolved in 2 ml of THF, and0.14 ml of a 3 N solution of methylmagnesium bromide in diethyl etherwas added. After stirring at room temperature for 30 minutes, thereaction solution was admixed with 10 ml of water and 30 ml of ethylacetate, and the organic phase was washed with 10 ml of saturated sodiumchloride solution, dried over Na₂SO₄ and concentrated by rotaryevaporation. The residue was purified in a purification laboratory bymeans of preparative HPLC, and the product-containing fractions werefreed of the solvent under reduced pressure. This gave the product (25.1mg) with a molecular weight of 369.5 g/mol (C₁₇H₂₇N₃O₄S); MS (ESI):m/e=370 (M+H⁺).

((S)-1-Phenylethyl)-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl)amine

A mixture of 194 mg of2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide and 737 mg of (S)-1-phenylethylamine was stirred at roomtemperature for 16 hours and then purified in a purification laboratoryby means of preparative HPLC. The combined product-containing fractionswere alkalized with 25% aqueous ammonia solution and extracted threetimes with 30 ml of ethyl acetate, and the combined organic phases weredried over MgSO₄ and concentrated by rotary evaporation. This gave theproduct (96 mg) with a molecular weight of 310.4 g/mol (C₁₅H₂₂N₂O₃S); MS(ESI): m/e=311 (M+H⁺).

2-(4-Fluorophenyl)-2-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)ethanesulfonamide

N-tert-Butylmethanesulfonamide

To a solution of 7.74 ml of methanesulfonyl chloride in 100 ml ofdichloromethane were added dropwise, at a temperature of 0° C., 23.12 mlof tert-butylamine. On completion of addition, the precipitate wasfiltered off and the filtrate was washed with 100 ml of 1 N aqueoushydrochloric acid, the organic phase was dried over MgSO₄ and thesolvent was removed under reduced pressure. The product (14.70 g) wasobtained with a molecular weight of 151.2 g/mol (C₅H₁₃NO₂S).

N-(tert-Butyl)-2-(4-fluorophenyl)-2-oxoethanesulfonamide

Under inert gas, 1.00 g of N-tert-butylmethanesulfonamide were initiallycharged in 20 ml of THF and then, at a temperature of −78° C., 9.00 mlof a 1.6 N butyllithium solution in hexane were added dropwise. Afterstirring with ice cooling for 5 minutes, the mixture was cooled again to−78° C., and a solution, likewise cooled to −78° C., of 1.33 ml ofmethyl 4-fluorobenzoate in 10 ml of THF was added dropwise. The mixturewas allowed to come to room temperature and stirred for 1 hour. Thereaction solution was admixed with 0.82 ml of acetic acid, diluted with50 ml of ethyl acetate, and washed with 40 ml of saturated aqueoussodium hydrogencarbonate solution and 40 ml of saturated aqueous sodiumchloride solution. The organic phase was dried over MgSO₄ andconcentrated by rotary evaporation. The crude product was purified bymeans of normal phase chromatography using a Flashmaster with ann-heptane/ethyl acetate gradient. The product-containing fractions werecombined and concentrated by rotary evaporation. This gave the product(662 mg) with a molecular weight of 273.3 g/mol (C₁₂H₁₆FNO₃S).

N-(tert-Butyl)-2-amino-2-(4-fluorophenyl)ethanesulfonamide

A solution of 0.66 g ofN-(tert-butyl)-2-(4-fluorophenyl)-2-oxoethanesulfonamide, 1.85 g ofammonium acetate and 0.17 g of sodium cyanoborohydride in 12 ml ofmethanol was stirred at 60° C. for 17 hours. After the removal of thesolvent under reduced pressure, the residue was taken up in 50 ml ofethyl acetate and washed twice with 30 ml of 0.5 N aqueous sodiumhydroxide solution and 30 ml of saturated aqueous sodium chloridesolution. The organic phase was dried over MgSO₄ and concentrated byrotary evaporation. The crude product was subjected to a chiralseparation.

Column: Chiralpak AD-H/39, 5 μm, 250×4.6 mm

Eluent: ethanol:methanol 1:1+0.1% diethylamine (30° C., flow rate 1ml/min)

Retention times: 4.787 min (enantiomer 1), 10.635 min (enantiomer 2)

The product-containing fractions were in each case combined andconcentrated by rotary evaporation. The two products (enantiomer 1: 269mg/enantiomer 2: 241 mg) were thus obtained with a molecular weight of274.4 g/mol (C₁₂H₁₉FN₂O₂S); MS (ESI): m/e=275 (M+H⁺). The absoluteconfiguration of the two products was not determined

2-(4-Fluorophenyl)-2-(5,5,6,6-tetramethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino)ethanesulfonamide

50 mg of N-(tert-Butyl)-2-amino-2-(4-fluorophenyl)ethanesulfonamideenantiomer 1 and 58 mg of2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine4,4-dioxide were dissolved in 1 ml of dichloromethane, and the mixturewas stirred at room temperature for 5 hours. The completeness of theconversion was checked by LCMS. Since no conversion had taken place yet,60 μl of N,N-diisopropylethylamine were added and the mixture wasstirred at room temperature overnight. The reaction solution was dilutedwith 20 ml of ethyl acetate and washed with 10 ml of 0.1 N hydrochloricacid and 10 ml of saturated aqueous sodium chloride solution. Theorganic phase was dried over MgSO₄ and concentrated by rotaryevaporation. The residue was dissolved in 1 ml of trifluoroacetic acidand dissolved at room temperature for 20 hours. After the removal of thesolvent under reduced pressure, the crude product was purified in apurification laboratory by means of preparative HPLC. Afterlyophilization of the product-containing fractions, the product (25.8mg) was obtained with a molecular weight of 407.5 g/mol (C₁₅H₂₂FN₃O₅S);MS (ESI): m/e=408 (M+H+).

The invention claimed is:
 1. A compound of the formula I

in which L is R1, —CH(R10)(R11); R10, R11 are each independently H, F,Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, COOH,COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅,(C₁-C₆)-alkylene-(R6), (C₃-C₈)-cycloalkylene-(R6),(C₁-C₆)-alkylene-(C₃-C₈)-cycloalkylene-(R6), (C₆-C₁₀)-aryl,(C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, —(C₆-C₁₀)-heteroaryl,(C₁-C₆)-alkylene-(C₆-C₁₀)-heteroaryl; where the aryl radical orheteroaryl radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON(C₁-C₆)-alkyl)₂, SF₅; R6 is OH, CF₃, CHF₂,CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅; R1 is (C₆-C₁₀)-aryl,(C₃-C₈)-cycloalkyl, (C₃-C₈)-carbocyclyl, where the aryl radical,cycloalkyl radical or carbocyclyl radical may be mono- to trisubstitutedby F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH,COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅;R2, R3, R4, R5 are each independently (C₁-C₆)-alkyl, CF₃, CHF₂, CH₂F,(C₁-C₆)-alkylene-OH, (C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, or R2 and R3, orR4 and R5, together with the carbon atom to which they are bonded form a3-8-membered saturated carbocyclic or heterocyclic ring which maycontain up to 2 further heteroatoms from the group of N, O and S; andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1,wherein L is R1, —CH(R10)(R11); R10, R11 are each independently F, Cl,Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, COOH,COO—(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅,(C₁-C₆)-alkylene-(R6), (C₃-C₈)-cycloalkylene-(R6),(C₁-C₆)-alkylene-(C₃-C₈)-cycloalkylene-(R6), (C₆-C₁₀)-aryl,(C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, —(C₆-C₁₀)-heteroaryl,(C₁-C₆)-alkylene-(C₆-C₁₀)-heteroaryl; where the aryl radical orheteroaryl radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅; R6 is OH, CF₃, CHF₂,CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl,SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅; R1 is (C₃-C₈)-cycloalkyl,(C₃-C₈)-carbocyclyl, where the cycloalkyl radical or carbocyclyl radicalmay be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F,NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅; R2, R3, R4, R5 areeach independently (C₁-C₆)-alkyl, CF₃, (C₁-C₆)-alkylene-O—(C₁-C₆)-alkylor R2 and R3, or R4 and R5, together with the carbon atom to which theyare bonded form a 3-8-membered saturated carbocyclic or heterocyclicring which may contain up to 2 further heteroatoms from the group of N,O and S; and pharmaceutically acceptable salts thereof.
 3. The compoundof claim 1, wherein L is R1, —CH(R10)(R11); R10, R11 are eachindependently (C₁-C₆)-alkyl, (C₁-C₆)-alkylene-(R6), (C₆-C₁₀)-aryl,(C₆-C₁₀)-heteroaryl; where the aryl radical or heteroaryl radical may bemono- to trisubstituted by F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN,OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl,SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅; R6 is OH, SO₂—NH₂; R1 is(C₃-C₈)-cycloalkyl, (C₃-C₈)-carbocyclyl, where the cycloalkyl radical orcarbocyclyl radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂; COOH, COO—(C₁-C₆)-alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅; R2, R3, R4, R5 areeach independently (C₁-C₆)-alkyl, CF₃, (C₁-C₆)-alkylene-O—(C₁-C₆)-alkylor R2 and R3, or R4 and R5, together with the carbon atom to which theybonded form a 3-8-membered saturated carbocyclic or heterocyclic ringwhich may contain up to 2 further heteroatoms from the group of N, O andS; and pharmaceutically acceptable salts thereof.
 4. The compound ofclaim 1, wherein L is R1, —CH(R10)(R11); R10 is (C₁-C₆)-alkylene-(R6),R11 is (C₆-C₁₀)-aryl, (C₆-C₁₀)-heteroaryl, where the aryl radical orheteroaryl radical may be mono- to trisubstituted by F, Cl, Br, CN; R6is OH, SO₂—NH₂; R1 is (C₃-C₃)-cycloalkyl, (C₃-C₈)-carbocyclyl, where thecycloalkyl radical or carbocyclyl radical may be mono- to trisubstitutedby F, Cl, Br, OH; R2, R3 are each independently (C₁-C₆)-alkyl, CF₃,(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl or R2 and R3 together with the carbonatom to which they bonded form a 3-8-membered saturated carbocyclic orheterocyclic ring which may contain up to 2 further heteroatoms from thegroup of N, O and S; R4, R5 are each independently (C₁-C₆)-alkyl, CF₃,(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, or R4 and R5 together with the carbonatom to which they are bonded form a 3-8-membered saturated carbocyclicring; and pharmaceutically acceptable salts thereof.
 5. A pharmaceuticalcomposition comprising the compound of claim 1, or pharmaceuticallyacceptable salts thereof, and a pharmaceutically acceptable carrierand/or excipient.
 6. The pharmaceutical composition of claim 5, furthercomprising at least one further active ingredient.
 7. The pharmaceuticalcomposition of claim 6, wherein said active ingredient is one or moreantidiabetics, active hypoglycemic ingredients, HMG-CoA reductaseinhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPARalpha agonists, PPAR alpha/gamma agonists, PPAR delta agonists,fibrates, MTP inhibitors, bile acid absorption inhibitors, CETPinhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACATinhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citratelyase inhibitors, squalene synthetase inhibitors, lipoprotein(a)antagonists, HM74A receptor agonists, lipase inhibitors, insulins,sulfonylureas, biguanides, meglitinides, thiazolidinediones,α-glucosidase inhibitors, active ingredients which act on theATP-dependent potassium channel of the beta cells, glycogenphosphorylase inhibitors, glucagon receptor antagonists, activators ofglucokinase, inhibitors of gluconeogenesis, inhibitors of fructose1,6-biphosphatase, modulators of glucose transporter 4, inhibitors ofglutamine:fructose-6-phosphate amidotransferase, inhibitors ofdipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroiddehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B,modulators of the sodium-dependent glucose transporter 1 or 2, GPR40modulators, inhibitors of hormone-sensitive lipase, inhibitors ofacetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase,inhibitors of glycogen synthase kinase-3 beta, inhibitors of proteinkinase C beta, endothelin-A receptor antagonists, inhibitors of I kappaBkinase, modulators of the glucocorticoid receptor, CART agonists, NPYagonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRFagonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1receptor antagonists, MSH (melanocyte-stimulating hormone) agonists, CCKagonists, serotonin reuptake inhibitors, mixed serotoninergic andnoradrenergic compounds, 5HT agonists, bombesin agonists, galaninantagonists, growth hormones, growth hormone-releasing compounds, TRHagonists, decoupling protein 2 or 3 modulators, leptin agonists, DAagonists, lipase/amylase inhibitors, PPAR modulators, RXR modulators orTR β agonists or amphetamines.
 8. A process for preparing apharmaceutical composition comprising mixing the compound of claim 1with a pharmaceutically suitable carrier and converting said mixture toa form suitable for administration.
 9. A method of treatinghyperglycemia comprising administering to a patient in need thereof atherapeutically effective amount of the pharmaceutical composition ofclaim
 5. 10. A method of treating diabetes comprising administering to apatient in need thereof a therapeutically effective amount of thepharmaceutical composition of claim
 5. 11. A method of treating insulinresistance comprising administering to a patient in need thereof atherapeutically effective amount of the pharmaceutical composition ofclaim
 5. 12. A kit consisting of separate packages of a) an effectiveamount of the compound of claim 1 and b) an effective amount of afurther active medicament ingredient.